Schisandra chinensis Turcz. Baill - Candiolicandioli.it/arch_bib/HRS/STR/SCH100 HANCKE-BURGOS... · Different aspects of the pharmacology of Schisandra chinensis fruit and dibenzo-

Ž .Fitoterapia 70 1999 451]471

Review

ž /Schisandra chinensis Turcz. BaillJ.L. Hanckea,U, R.A. Burgosb, F. Ahumadab

aLaboratorios Garden House, A¨. Presidente J. Alessandri 12310, San Bernardo, Santiago, ChilebInstituto de Farmacologıa, Facultad de Ciencias Veterinarias, Uni ersidad Austral de Chile, P.O.´

Box 567, Valdi ia, Chile

Received 16 March 1999; accepted 1 June 1999

Abstract

Different aspects of the pharmacology of Schisandra chinensis fruit and dibenzo-w xa,c cyclooctene lignans from this plant are reviewed focusing in particular on the antihepa-totoxic, antioxidant and antitumoural activities, and on the effects on physical performanceand on the central nervous system. Q 1999 Elsevier Science B.V. All rights reserved.

Keywords: Schisandra chinensis; Lignans; Antioxidant activity; Antihepatotoxic activity; Antitumoralactivity; Physical performance; CNS

1. Botany

Ž . Ž .Schisandra chinensis Turcz. Baill Schisandraceae grows wild in the mostŽ .Eastern parts of Russia Primorsk and Chabarowsk regions , the Kuril islands,

w xsouthern Sachalin and also north-eastern China, Korea and Japan 1 . Schisandraspecies grow mainly in China, Japan, the Himalayas and Jawa. The seeds and the

w xfruit are the parts used in medicine 2]4 . S. chinensis is a monoecius liana withattractive leaves and a woody stem. The winding stem, reaching 10]15 m in lengthand 1.2]1.5 cm in diameter, is twisting around the trunks of trees, climbing to theirtop. The leaves are alternate, elliptic, cuspidate, with a wedge-shaped base. Theflowers are white or slightly cream-coloured, wax-like, unisexual with a pleasant

U Corresponding author. Tel.: q56-2-5281411; Fax: q56-5293646.Ž .E-mail address: [email protected] J.L. Hancke

0367-326Xr99r$ - see front matter Q 1999 Elsevier Science B.V. All rights reserved.Ž .PII: S 0 3 6 7 - 3 2 6 X 9 9 0 0 1 0 2 - 1

( )J.L. Hancke et al. r Fitoterapia 70 1999 451]471452

smell. The flowers are in clusters of 2]5. When the fruit is ripening, the receptacleis substantially lengthened and turned into a pedicle with the appearance of agrape cluster, 6]8 cm long with several bright red fruits. The fruits, ripen inSeptember]October, have an almost spherical shape and contain 1]2 yellow seeds.The skin and pulp taste sour and sweet. The kernel is pungent, bitter and overall

Žsalty. It is called in mandarin ‘wu-wei-zi’, literal English translation: five-taste. Ž .fruit , in Japanese ‘Gomishi’, in Korean ‘Omicha’ Chinese Materia Medica .

w xExperiences of its cultivation were reported 1 .In western botany the Chinese wu-wei-zi was first named Kadsura chinensis in an

1832 publication of the Russian botanist Nikolai S. Turczaninov. In 1856, to honourŽ .his most famous colleague K.J. Maximowicz 1827]1891 , the Russian botanist

Ž .Franz J. Ruprecht 1814]1870 created a new genus called Maximowiczia andcalled the plant Maximowiczia chinensis. In 1866, the French botanist H.E. BaillonŽ .1827]1895 transferred the plant to the genus Schisandra and since that time the

Ž . w xplant has been known as S. chinensis Turcz. Baill. 3 . The generic nameSchisandra is derived from the Greek schizein, meaning ‘to cleave’ and andros,‘man’, referring to the cleft or separate anther cells on the stamens of S. coccinea.

Ž .Fructus schisandrae, of the Chinese Pharmacopoeia, consists of two members: 1 S.Ž . Ž . Ž .chinensis Turcz. Baill. Northern Schisandra and 2 S. sphenanthera Rehd. et

Ž . w xWils. Southern Schisandra 2 .

2. Chemistry

w x ŽMany dibenzo a,c cyclooctene derivatives, present in different quantities fruit.and seeds: 7.2]19.2%; stems: 1.3]10% have been isolated from S. chinensis

w x5]20 . Some of the main structures are shown in Table 1. Biosynthetic precursorsto the dibenzocyclooctene derivatives, such as pregomisin and epigalbacin, have

w xbeen also isolated 20 . The fruits also contain about 1.5% sugars, tannins, colourŽsubstances and about 3% of essential oils citral, b-chamigrene, b-camigrenol,

. Ž .b -bisabolene, sesquicarene , organic acids citric, malic, fumaric and tartaric acid ,2w xvitamin C and E, and metals such as copper, manganese, nickel and zinc 21 .

3. Pharmacology

w xS. chinensis is officially listed in the Chinese Pharmacopoeia 22 and indexed asa tonic and sedative. It is also listed in the ‘Shen Nong Ben Tsao Ching’ book, year

Ž .1596 2697 BC as a superior drug that helps in coughs and prevents asthma. It wasw xfirst reported in Divine Husbandman’s Classic of the Materia Medica 3 . Accord-

Ž .ing to Chinese philosophy the drug has sour and warm properties. It: a enters theŽ .lung and kidney channels and the stomach meridians; b contains the leakage of

Žlung ‘Qi’ and stops coughing used for deficient lung and kidney patterns with. Ž . Žcough and wheezing ; c restrains the ‘Essence’ and stops diarrhoea used for

. Ž .nocturnal emission, spermatorrhea, deficiency of the spleen and kidneys ; d stops

( )J.L. Hancke et al. r Fitoterapia 70 1999 451]471 453



Žexcessive sweating used for deficient ‘Yang’ spontaneous sweating or deficient. Ž . Ž . w x‘Yin’ night sweat ; e calms the spirit used for forgetfulness and insomnia 4,10 .

S. chinensis fruit has been used for a long time in the Far East as a stimulatingand fortifying agent in cases of physical exhaustion, and to inhibit fatigue. TheNanajs tribals used S. chinensis dried berries to combat fatigue in their hunting

w xtrips 1 .A monograph on S. chinensis preparations was introduced officially to the

w xRussian Pharmacopoeia in 1961 23 .

3.1. Antihepatotoxic effect

Ž .Several reports indicate that S. chinensis dried fructus and seed is an effectivew xliver protective drug 24]26 . In experimental models, Glutamic Piruvic Transami-

Ž . Ž .nase GPT activities induced by carbon tetrachloride CCl or paracetamol in4mice, thiacetamide in rats, and ethinylestradiol 3-cyclopentylether in rabbits werereduced by oral administration of the ethanol extract of the seed of S. chinensisŽ . w x1]10 grkg prior to and after the administration of the hepatotoxic agents 24,25 .The alcoholic extract of S. chinensis kernels reduced elevated GPT levels in micetreated with CCl or thioacetamide, while a water extract of the kernels and an4

w xethanol extract of the shells of the seed were ineffective 21 . Primary cultured rathepatocytes treated with 0.1]1 mgrml of either an ether, ethyl acetate, methanolor water extract of S. chinensis fruit were effective in reducing the galactosamine

w xand CCl -induced cytotoxicity 20 . Different lignans isolated from S. chinensis4w xhave been associated to this antihepatotoxic effect 27,28 . Seven lignans isolated

from S. chinensis kernels and tested for antihepatotoxic activity have been shownw xeffective liver protecting drugs 23 . Most of them prevented the elevation of serum

GPT levels and the morphological changes of the liver, such as inflammatoryŽ .infiltration and liver cell necrosis induced by CCl . Gomisin B 50 mgrkg, p.o ,4

Ž . Ž .gomisin A, 50 mgrkg, p.o. , schisandrin C 50]100 mgrkg, p.o. , schisandrin BŽ . Ž . Ž50]100 mgrkg, p.o. deoxyschisandrin 200 mgrkg, i.p. , g-schisandrin 50]100

. Ž .mgrkg, p.o. and gomisin C 200 mgrkg, i.p. decreased the GPT levels after CCl4w x Ž .27 . Gomisin B, gomisin A and schisandrin at doses of 100 mgrkg, p.o. were also

w xeffective against thiacethamide-induced liver damage in mice 21,27 .In fasting mice, the lignans stimulated the glycogen synthesis, the order of the

activity being gomisin A ) deoxyschisandrin s g-schisandrin. The activity ofŽ .gomisin A was comparable to that of cortisone 100 mgrkg, p.o. . Since similar

results were obtained in adrenalectomized mice, the effect of these lignans onw xglycogenesis seems not mediated by the adrenals 21,27 .

Ž .Pretreatment of male rats with gomisin A 50 mgrkg, i.p. prevented the rise inŽ .GPT and Glutamic Oxaloacetic Transaminase GOT and hepatic necrosis of cells

w x Žinduced by acetaminophen 29 . The repeated administration of gomisin A 30 or.100 mgrkg, p.o., daily for 4 days induced an apparent increase of liver weight in

w xliver-injured and normal rats 30 . Gomisin A suppressed the increase in serumtransaminase activity and the appearance of histological changes such as hepato-cyte degeneration and necrosis, inflammatory cell infiltration and fatty deposition


w xinduced in liver by CCl , D-galactosamine or D-,L-ethionine 30 . Gomisin A4decreased serum triglycerides and lipid contents of the liver. It also increasedmicrosomal cytochrome b , P-450, NADPH cytochrome C reductase, aminopyrine5N-demethylase and 7-ethoxycoumarin O-dethylase and decreased 3,4-benzo-w x w xa pyrene hydroxylase 30 .

A hepatoprotective effect of deoxyschisandrin, g-schisandrin, schisandrin C,gomisin A, and schisandrin has been associated to their inhibitory effect onCCl -induced lipid peroxidation and the binding of CCl metabolites to lipids of4 4

w xthe liver microsomes 31]33 .w x w xSchisandrin B 34 and schisanhenol 35 under oxidative stress, and gomisin A in

w ximmunologic liver injury 36 increased the membrane stability of hepatocytemembrane. This effect can be related to a stimulating effect on the hepatic-gluta-

w xtione antioxidant system 37 and may involve the enhancement of mitochondrialw xglutathione redox status in rats 38 .

Ž .It is also suggested that gomisin A 50 mgrkg, i.p. possesses a liver functionenhancing property in normal and injured liver, and that its preventive action onCCl -induced cholestasis is sustained by the secretory function of the bile acids4

w xindependent fraction 39 .Gomisin A and schisandrin B induced hypertrophy and mild hyperplasia, aug-

w14 xmenting the liver weight. C Phenylalanine incorporation, protein content, andw xhepatic microsomal cytochrome P-450 content were enhanced 40,41 . Gomisin A

Ž .10]100 mgrkg, p.o. for 4 days also increased the liver regeneration in rats afterpartial hepatectomy, increased the regeneration rate of the liver cells, and im-

Ž .proved the serum retention rate of the foreign dye sulfobromophtalein BSP ,w xwhich was dose-dependent 42 . In addition, gomisin A also enhanced the incor-

w14 xporation of C phenylalanine into liver protein and shortened the hexobarbital-induced sleeping time. These changes caused by gomisin A are similar to those of

w xphenobarbital 42 . However, gomisin A is distinctly different from phenobarbitalin the finding that phenobarbital diminished the survival of CCl -intoxicated mice,4

w xbut gomisin A did not 42 .Ultrastructural studies of liver tissue using the transmission electron microscope

revealed an increase in rough and smooth endoplasmic reticulum in the groupsŽ .receiving gomisin A 100 and 300 mgrkg per day . Gomisin A accelerated both the

proliferation of hepatocytes and the recovery of liver function after partial hepatec-tomy and increased hepatic blood flow. It is thought that the liver enlargementcaused by repeated administration of gomisin A is associated with the proliferation

w xof endoplasmic reticulum 42 .Ž .Gomisin A 10 or 30 mgrkg, p.o. for 3 or 6 weeks suppressed the fibrosis

proliferation and accelerated both the liver regeneration and the recovery of liverw xfunction after partial hepatectomy in CCl -induced chronic liver injury in rats 43 .4

Also, gomisin A regenerated the liver tissue after partial hepatectomy by enhanc-ing ornithine decarboxylase activity, which is an important biochemical event in the

w x Žearly stages of liver regeneration in rats 44 . Gomisin A 100 mgrkg, p.o. daily for.14 days promoted hepatocyte growth after mitosis during regeneration of partially

resected rat liver, inducing directly or indirectly an enhanced activation of the


proliferative processes of non-parenchimal cells that involved an increase in c-mycw xproduct, a gene that precedes DNA replication in proliferating cells 45 .

The effects of gomisin A on immunologically induced liver injuries have beeninvestigated in vivo and in vitro. Following injection of a small dose of lipopolysac-charide in mice previously treated with heat-killed Propionibacterium acnes, most of

Ž .the animals died with acute hepatic failure. Gomisin A 5]50 mgrkg, p.o reduceddose-dependently the mortality of mice with acute hepatic failure. Histologically,necrosis was suppressed by gomisin A, but infiltration of non-specific inflammatorycells was not affected. In in vitro experiments, the liver cells were injured by

Ž .antibody-dependent cell-mediated cytotoxicity ADCC reaction or activation ofmacrophage in vitro . Inhibition of the isolated liver cell injuries induced by ADCCreaction or activation of macrophages in vitro, suggested that gomisin A can be

w xmarkedly protective against immunological liver injuries 46 . In guinea pigs sensi-Žtised with trinitrophenylated liver macromolecular protein fraction, gomisin A 50

. w xmgrkg, p.o. was effective in reducing the acute hepatic failure 47 . Also the acutehepatic failure induced by heat-killed Propionibacterium acnes followed by a smallamount of Gram-negative lipopolysaccharide was prevented after 4 weeks of

Ž . w xgomisin A 60 mgrkg per day for 4]10 weeks administration 48 . The survival ratewas 80% as compared to 5% of the control group. In Long Evans Cinnamon rats,spontaneously developing hepatitis, treatment with gomisin A did not modify thedeath rate, but the time of survival was increased by 7]10 weeks as compared with

w xthe control group 49 .Leukotrienes are potent inflammatory agents that are thought to play a role in

w xinflammatory liver diseases 50 . In inmunological hepatic failure, mononuclearŽcells are the predominant cells producing leukotrienes. Gomisin A 0.1 mgrml,

7 .added to 10 macrophage cellsrml suspension produced on the biosynthesis ofleukotrienes stimulated in rat peritoneal macrophages by Ca2q ionophore A2318an inhibitory effect which may be partially associated with its antihepatotoxic effectw x51 .

3.2. Antioxidant and detoxificant effect

w xThe antioxidant effect of S. chinensis is attributed to the dibenzo a,c cyclooctenew xlignan constituents 52,53 . In in vitro studies, induction of antioxidative enzymes

has been observed with S. chinensis lignans which inhibited the lipid peroxidationŽ .measured by means of malondialdehyde MDA formation induced by ironrcy-

Ž .steine in rat liver microsomes: at 1 mM concentration, schisanhenol, S y -schi-Ž .sandrin C and S y -schisandrin B were shown to be more potent than vitamin E

w x Ž . Ž .35 . Schisanhenol 1 mM and schisandrin B 1 mM also inhibited gossypol-in-duced superoxide anion generation in rat liver microsomes. The preventive oral

Ž .administration 200 mgrkg, once daily for 3 days of either schisanhenol orŽ .schisandrin B reduced liver MDA formation induced by 50% ethanol 15 mlrkg

w x54 . In vitro, schisanhenol demonstrated an oxygen scavenging activity in ironrcy-w x Ž .steine and NADPHrascorbic acid method, 55 and CCl -OH and -CCl -induced4 3

w xlipid peroxidation in hepatocytes 34,56 . The release of GPT and lactate dehydro-


Ž .genase LDH was also reduced. As a consequence, the hepatocyte viability wasw xincreased as well as the integrity of the hepatocyte membrane 35 . Moreover, the

hepatoprotective effects of Schisandra lignans may be attributed to the enhance-ment of the hepatic antioxidant system. In fact, schisandrin B and schisanhenolwere also able to increase superoxide dismutase, catalase activities in rat liver

w x Ž .cytosol, 54 and the function of the hepatic reduced glutathione GSH anti-oxi-w xdant system 37 . Intragastric pre-treatment of female Balbrc mice with schisan-

Ž .drin B 4]16 mgrkg per day for 3 days caused dose-dependent increases inŽ . Ž .hepatic glutathione S-transferase GST and glutathione reductase GRD activi-

ties. In other experiments, 24 h after the last dose of schisandrin B, all rats wereŽ .treated with CCl 0.1 mlrkg . The activities of glucose-6-phosphate dehydroge-4

Ž . Ž .nase G6PDH , Se-glutathione peroxidase GPX , and gamma-glutamylcysteineŽ .synthetase GCS are down-regulated to varying degrees in a dose-dependent

w xmanner by schisandrin B 37 . The beneficial effect of schisandrin B on the hepaticGSH antioxidant system is more evident after CCl challenge. The hepatoprotec-4tion was associated with significant enhancement in hepatic GSH, as indicated bythe substantial increase in tissue GSH levels and the corresponding decrease in the

w xsusceptibility of tissue homogenates to GSH depletion 37 . The hepatoprotectiveŽ . Ž .effect of schisandrin B 8 mgrkg, i.p. was not affected by 1,3-bis 2-chloroethyl -1-

Ž .nitrosourea, an inhibitor of GRD, at a dose of 2 mmolrkg i.p. in female Balbrcmice. The mechanism of hepatoprotection by schisandrin B may involve theenhancement of mitochondrial glutathione redox status greatly impaired by CCl -4

w xintoxication 38 .Interestingly, while well known antioxidant agents such as a-tocopherol acetate

did not protect against hepatic damage induced by other hepatotoxins such asaflatoxin B or Cd, S. chinensis reduced the hepatotoxic effect of these agents in a1

Ž . w xnon-selective manner Tables 2 and 3 57 . In fact, pre-treatment with a lignanenriched extract of S. chinensis fruit stimulated the hepatic antioxidantrdetoxifica-tion system, as shown by increased hepatic GSH levels as well as hepatic GRD and

w xGST activities in rats 57 .Some comparative studies in female Balbrc mice have shown that schisandrin B

Ž .12 mgrkg per day, p.o. for 3 days increased the hepatic mitochondrial-GSH level,Ž .whereas butylated hydroxytoluene BHT decreased it. However, both schisandrin

B and BHT increased, albeit to a different extent, the activity of mitochondrialw x ŽGRD, particularly after CCl challenge 58 . Pre-treatment with schisandrin B 124

.mgrkgrday, p.o. for 3 days sustained the hepatic mitochondrial GSH level inCCl -intoxicated mice and protected against CCl -induced hepatotoxicity, while4 4BHT pre-treatment did not. Moreover, while both schisandrin B and BHT in-

Ž .creased hepatic ascorbic acid vitamin C level in control animals, only schisandrinB pre-treatment sustained a high hepatic vitamin C level in CCl -intoxicated mice.4Also, schisandrin B pre-treatment prevented the CCl -induced decrease in the4hepatic vitamin E level. However, schisandrin B inhibited NADPH oxidation in

Ž .mouse liver microsomes incubated with CCl 10 mM in vitro, whereas, BHT4stimulated this oxidation. The ability to sustain the hepatic mitochondrial GSHlevel and the hepatic vitamin C and vitamin E levels may represent a crucial


Tab

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0.14

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Table 3aThe effect of S. chinensis and vitamin E pre-treatment on Cd-induced hepatotoxicity in rats

PlasmaHepatic tissueGOTMalondialdehyde GSH GSH reductase GSH S-transferaseŽ .UrlŽ Žnmolrmg wet mUrmg wet

. .tissue tissue

Control 0.044 " 0.002 7.04 " 0.22 4.90 " 0.26 98.4 " 11.3 37.4 " 1.8b bCd 0.054 " 0.005 6.55 " 0.24 4.34 " 6.32 54.6 " 11.1 96.6 " 16.2

S. chinensisc b,c b,c cqCd 0.042 " 0.003 7.07 " 0.48 7.60 " 0.16 193.0 " 3.9 57.5 " 7.4

d c,d b,dVit. E q Cd 0.049 " 0.003 6.03 " 0.59 4.55 " 0.24 91.8 " 9.5 85.6 " 7.3

a Values are mean "S.E.M., n s 5; bP - 0.05 vs. control; cP - 0.05 vs. Cd; dP - 0.05 vs. S.chinensis q Cd. Data were analysed using one-way ANOVA followed by Duncan’ s multiple range test.Ž w x .Reproduced from Ip S.P. et al. 57 , with permission of Pharmacology and Toxicology .

antioxidant property of schisandrin B in protection against CCl hepatotoxicity4w x58 .

The effects of schisandrin B and vitamin E have been compared on ferricŽ 3q.chloride Fe -induced oxidation of erythrocyte membrane lipids in vitro and

CCl -induced lipid peroxidation in vivo. Vitamin E produced a pro-oxidant effect4at 110 mM and a biphasic effect at 1.0 mM on the Fe3q-induced TBARSŽ .thiobarbituric acid reactive substances in human erythrocyte membranes; thepro-oxidant effect, lasting 20 min, was followed by a complete suppression of

Ž .TBARS antioxidant effect. Schisandrin B 110 mM was capable to inhibit TBARSw x Ž .formation 59 . Pre-treatment with vitamin E 3 mmolrkg per day, p.o. for 3 days

did not protect against CCl -induced lipid peroxidation and hepatocellular damage4Žin mice, whereas schisandrin B pre-treatment 0.3] 3.0 mmolrkgrday, equivalent

.to 1.2]12 mgrkg per day, p.o. for 3 days produced a dose-dependent protectiveŽ . w xeffect on the CCl -induced hepatotoxicity Table 4 59 .4

The scavenging effects of different structures and configurations of schisandrinson active oxygen radicals have been demonstrated using active oxygen radicalsfrom human polymorphonuclear leukocytes stimulated with phorbol myristateacetate. The scavenging effects of schisandrins depend on the stereoconfigurations,

Ž . Ž .the effect of S y -schisandrin B being stronger than that of R q -schisandrin andw xthat of schisandrin C stronger than that of schisandrin B 60 . This difference may

be explained by the dioxymethyl group that captures electrons facilitating radicalw x Ž .attack 60,61 . Surprisingly, the scavenging effect of S,R " -schisandrin B was

Ž . Ž .stronger than that of either S y - or R q -schisandrin B. The reason for thisw xeffect is unknown 61 .

Ž .Another lignan, schisanhenol 1 mmolrl was able to scavenge oxygen radicalsproduced by human neutrophils stimulated by tetradecanoylphorbol acetate. InFenton reaction system, the inhibitory rate of hydroxyl radical by schisanhenol was34.4%. In xanthine]xanthine oxidase and UV-irradiation of riboflavin systems,


Table 4aŽ .Effects of Schisandrin B S-B and vitamin E pre-treatment on CCl -induced hepatotoxicity in mice4

MDA Plasma ALTŽ . Ž .pmolrmg tissue Url

Control 60 " 1 14.4 " 0.7b cCCl 87 " 6 12 526 " 7964

S-B q CCl4d e( )0.5 mmolrkg 68 " 3 1008.4 " 447.4 92d e( )3.0 mmolrkg 56 " 2 24.1 " 4.6 99

Vit. E q CCl43.0 mmolrkg 89 " 9 12 904 " 873

a Values are mean " S.E.M., n s 5; bP - 0.05; cP - 0.001 vs. control; dP - 0.05; eP - 0.001 vs.ŽCCl Student’s t-test. The italic number in parentheses is the percent of protection. Reproduced from4,

w x .59 , with permission of Molecular and Cellular Biochemistry .

schisanhenol scavenged superoxidase anion radical by 26.1% and 21.9%, respec-w xtively. In all these systems, schisanhenol was more potent than vitamin E 55 .

3.3. Anticarcinogenic effect

w x Ž .Benzo a pyrenes BPs are well known carcinogens, widely distributed in thew xenvironment 62,63 . The elimination of these polycyclic aromatic hydrocarbons

w xfrom the body requires their conversion to water-soluble metabolites 64 . Some ofthe enzymes involved in BP metabolism, such as cytochrome P-450, epoxide

Ž . Ž .hydratase EH , and arylhydrocarbonhydroxylase AHH are induced by varioussubstances found in edible plants. There is some evidence that consumption ofvegetables like sprouts, cabbages, broccoli, alfalfa and fibres may reduce the

w xincidence of stomach and colon cancers 65,66 .The effect of deoxyschisandrin, g-schisandrin, schisandrin C, gomisin A, B and C

Ž .orally given 100]200 mgrkg per day for 3 days to male rats has been studied invitro on liver microsomal monooxygenases and epoxide hydrolase. Among thesecompounds, schisandrin B, schisandrin C, gomisin A and biphenyl dimethyl dicar-

Ž .boxylate BDD , a synthetic derivative of gomisin C, significantly increased rat livercytochrome P-450 concentration, NADPH-cytochrome C reductase, benzo-

Žphetamine and aminopyrene demethylase activities. Four compounds g-schi-.zandrin, schizandrin C, gomisin A and BDD also markedly stimulated prolifera-

tion of smooth endoplasmic reticulum of liver cells from rats treated with schisan-w xdrin B 32 .

Ž .It is known that phenobarbital PB; 80]100 mgrkg, p.o. for 3 days -inducedmicrosomal monooxygenase activities are preferentially inhibited by metyrapone,an enzymatic inhibitor of cytochrome P-450 enzymes involved in the synthesis ofadrenocorticosteroids. Schisandrin B, schisandrin C, gomisin A, and BDD inhibited


aminopyrene demethylase activity of liver microsomes in a similar manner. DualŽ .induction by gomisin A 100]200 mgrkg, p.o. and PB decreased the mutagenicity

of BP via a decreased covalent binding of BP metabolites to DNA. Gomisin A alsodecreased the capacity of BP-induced rat microsomes to activate BP to its muta-

w xgenic metabolites 31,32 .Using male mice of the strain C57B16 that responded with a marked induction

Žof hepatic microsomal benzopyrene hydroxylase activity, S. chinensis fructus fine.powder, 5% in diet for 14 days induced a threefold increase in cytochrome P-450.

EH was stimulated significantly by S. chinensis. It is known that the addition ofpurified EH to the Salmonella mutagenecity Ames test reduces BP mutagenicity by

Ž .30]50%. Total BP metabolism was significantly increased 1.6-fold in the S.Ž .chinensis 1 mgrml group. Phenol II formation relative to total metabolites was

significantly increased in the S. chinensis group as compared to the control groupw x Ž .67 . Both 7-ethoxycoumarin O-de-ethylase ECD and aryl hydrocarbon hydroxy-

Ž . w xlase AHH activities were also increased significantly 68 . The binding of aflatoxinw xto DNA was diminished by S. chinensis 68 .

The effect of gomisin A on hepatocarcinogenesis caused by 39-methyl-4-dimeth-Ž .ylaminoazobenzene 39-MeDAB in male Donryu rats has been investigated.

Ž .Gomisin A 30 mgrkg per day, p.o. for 5 weeks significantly inhibited theŽ .appearance in the liver of foci for glutathione-S-transferase placental form GST-P ,

a marker enzyme of preneoplasm. Gomisin A decreased the number of hepaticaltered foci such as the clear cell and basophilic cell type foci in the early stagesw x Ž .69,70 . Gomisin A 30 mgrkg per day, p.o. decreased the concentration of39-MeDAB-related azo dyes in the liver, and increased their excretion in the bile.After the withdrawal of 39-MeDAB, carcinogen related azo dyes were not detectedeither in the liver or the bile, but the proportion of diploid nuclei, thoughdiminished, remained high. It seems that gomisin A improved liver function by

w xreversing abnormal ploidization 71 .Ž .Gomisin A 0.03% in diet for 10 weeks inhibited the development of preneopla-

sic liver lesions. In fact, gomisin A inhibited the level of GST-P, and the numberand size of GST-P positive foci increased in the liver after treatment with39-MeDAB. Moreover, although the population of diploid nuclei was increased andthat of tetraploid nuclei was decreased by pre-treatment with 39-MeDAB, gomisin

w xA reverted this effect to near the normal ploidy pattern 71 . This suggests thatgomisin A may inhibit the hepatocarcinogenesis induced by 39-MeDAB by enhanc-ing the excretion of the carcinogen from the liver and by reversing the normal

w xcytokinesis 72 .Ž .Gomisin A 30 mgrkg, p.o. daily for 5 weeks inhibited the increase in serum bile

acid concentration induced by the administration of other tumour promotors suchŽ . w xas deoxycholic acid DCA 73 . Although hepatocarcinogenesis has been reported

to be promoted by exogenous administration of bile acids, the relation of en-w xdogenous bile acids to hepatocarcinogenesis is not completely understood 74,75 .

Ž .The oral administration of gomisin A 30 mgrkg significantly inhibited theincrease of serum bile acids, especially DCA, and the appearance of preneoplastic

Ž .lesions number and area of GST-P-positive foci in the liver , induced by 39-


Fig. 1. Inhibitory effect of gomisin A on the promotion of skin papillomas by 12-O-tetrade-Ž .canoylphorbol-13-acetate TPA in DMBA-initiated mice. From 1 week after initiation by a topical

application of 50 mg of DMBA, 2.5 mg of TPA was applied twice weekly. Topical application of gomisinŽ .A 5 mmol and vehicle was performed 30 min before each TPA treatment. Data are expressed as

Ž . Ž .percentage of mice bearing papillomas A and average number of papillomas per mouse B .Ž w x .Reproduced from Yasukawa K. et al. 77 with permission of S. Karger AG, Basel .

MeDAB. These results confirm that DCA is an endogenous risk factor forhepatocarcinogenesis and suggest that the anticarcinogenic effect of gomisin A

w xmay be based on improving metabolism of bile acids 76 .Ž . Ž .Application 1 mgrear of 12-O-tetradecanoylphorbol-13-acetate TPA , a tu-

Žmour-promoting agent, to mice induces inflammation. Local application 0.6.mgrear of gomisin A inhibited TPA-induced inflammation in mice. Also gomisin J

and schisandrin C inhibited the inflammation induced by TPA in mice. The ED50of these compounds ranged between 1.4 and 4.4 mmol, gomisin A showing thestrongest inhibitory effect. Furthermore, at 5 mmolrmouse, it markedly suppressed

Ž .the promotion effect of TPA 2.5 mgrmouse on skin tumour formation in micew x Ž . w x Žfollowing initiation with 7,12-dimethylbenz a antracene 50 mgrmouse 77 Fig.

.1 .

3.4. Effects on physical performance

A number of Russian reports indicate that S. chinensis is able to counteract theeffect of fatigue, increase endurance, and improve the physical performance of

w xsportsmen 78 , but no controlled studies were done in the western world until thelate 1980s. To validate the hypothesis that this plant can improve the physicalrecovery, in a first series of trials, 50 g of S. chinensis fructus dried extract wereadministered to thoroughbred horses prior to a 800-m race at maximum speed, andto polo horses submitted to a 12-min gallop at a speed of 400 mrmin, or a 5-min

w xgallop at a speed of 700 mrmin 79 . S. chinensis counteracted significantly theanticipatory respiratory and cardiac frequency as compared to the control group.


Ž . Ž .Fig. 2. Effect of S. chinensis treatment on lactate a and glucose b plasmatic profile in race horsesŽ .subjected to effort. Arrows represent the first record after the exercise 7 min . Values are mean "

U UU Ž . ŽS.E.M., n s 5; P - 0.05; P - 0.01 vs. control saline ; Student’s t- test. Reproduced withw x.permission of Fitoterapia 80 .

Also, the seric lactic acid was reduced and the plasmatic glucose increased in S.chinensis treated horses. Interestingly, the horses treated with S. chinensis wereable to complete the race at an average of 1.8 s faster, indicating an improvement

w xin the physical performance of the horses 79]81 . On a second series of studies,Ž .the effect S. chinensis fructus dried extract single dose of 6 g, p.o. was studied in

race and spring horses in order to asses whether the type and intensity of thew xexercise is critical for the effect 80 . S. chinensis was capable of reducing signifi-

cantly the heart rate and respiratory frequency at different time intervals after thetrial, particularly in race horses. Plasmatic glucose concentration increased signifi-cantly in both types of exercise. The plasmatic concentration of lactic acid wasreduced in S. chinensis treated horses as compared to the controls, this decrease

w x Ž .being again more evident in race horses 80 Fig. 2 .The liver accomplishes important functions in the metabolisation of lactic acid,

and its functionality determines to a great extent the performance level of horses.Accordingly, an increase of the transaminase activity results in an impairment of

w xthe horses’ physical performance 82 . As it is known that S. chinensis decreases thew xhepatic transaminases activity 20,21 , the hypothesis was made that S. chinensis

could lower the seric levels of transaminases and, thus, reverse the impairedw xperformance of horses 83 . Indeed, an association between poor performance and

w xhigh seric levels of hepatic enzymes in sport horses was shown 82 . Moreover,Ž . w xtraining leads to an increment of creatinine phosphokinase CPK 82 , an enzyme

present in the striated and heart muscle, and intense anaerobic exercise can lead to


Ž . Ž .Fig. 3. Effect of S. chinensis on GOT a and CPK b serum levels in poorly performing horses.U UU Ž .Values are mean " S.E.M., n s 12; P - 0.05; P - 0.01 vs. control saline , Student’ s t- test.

Ž w x.Reproduced with permission of Phytomedicine 83 .

muscle skeletal damage, with increase in seric level of CPK and transaminases.Poorly performing sport horses with long lasting high levels of g-gluta-

Ž .myltransferase GGT , GOT and CPK were orally administered 3 g of S. chinensisdried extract, during 14 days. S. chinensis reduced the levels of GGT and GOT in

w xthe serum at day 7 and 14 after administration 83 . Surprisingly, the CPK levelswere also reduced by day 7 and 14 after administration indicating that these

w xanimals presented a muscular damage that could be reverted with S. chinensis 83Ž . w xFig. 3 . Simultaneously, Ko et al . 84 reported a protective effect against physicalexercise-induced muscle damage and a myocardial protective effect in rats pre-

Žtreated with a lignan enriched extract of S. chinensis fruit 0.8 grkg day, p.o for 3. w xdays 85 . Protection was associated with a significant enhancement in the hepatic

w xantioxidant status, as assessed by GSH and MDA concentrations 84]87 . Fig. 4summarises the possible effects of S. chinensis on the metabolic pathways duringmaximum physical effort. S. chinensis reduced the hepatic damage leading to a

Ž .decrease in transaminases GOT, GGT . As a consequence, gluconeogenesis char-acterised by an increase in seric glucose level was improved. On the other hand, S.chinensis reduced the striated muscle damage via a decrease of seric CPK level andreduced the seric lactate levels, probably by an antioxidant effect.

( )3.5. Acti ity on central ner¨ous system CNS

Activation of the CNS by S. chinensis has been evidenced during electroen-cephalographic examination. In particular, S. chinensis, antagonised the effect ofsubstances supressing the CNS such as barbiturates, chloral hydrate, aminazine,

w x Ž .and halothane 88,89 . Schisandra lignans 1]5 mgrkg, i.p. antagonised the effectw xof hexenal and chloral hydrate in rats 88 . The CNS activating effect of S. chinensis

was observed even under the presence of antagonist to dopamine receptors DA 2


Fig. 4. Antioxidant effect of S. chinensis on liver and striated muscle during exercise.

w x w x88 . However, potentiation of phenobarbital sleeping time 90 would indicate thatS. chinensis has a depressing action on the CNS. This could be explained by thepresence in the tested extracts of different concentrations of schisandrol A which isknown to prolongue the sleeping time induced by phenobarbital and decrease the

w xspontaneous motor activity in mice 91 .The cholinergic system is also significantly influenced by S. chinensis. A crude

Ž .petrol ether fruit extract 10]30 mgrkg, p.o. decreased the convulsant thresholdand potentiated the antidiuretic action of nicotine and potentiated the excitatoryaction of carbachol on the intestine in rats. This petrol ether extract potentiated

Ž . w xthe action of reserpine only at higher doses 1.5 grkg 92,93 . This extract affectedmostly the cholinergic system, with a biphasic response. At dose of 280 mgrkg p.o.,it showed an indirect nicotinomimetic action potentiating the carbachol intestinal

Ž . w xmotility, whereas, a higher dose 840 mgrkg, p.o. had a cholinolytic effect 93 .Schisanhenol and schisandrin B have been shown to protect peroxidative damage

w x Ž y4 .of aging and ischemic rat brain 94 . Schisanhenol and schisandrin 10 Mcompletely inhibited the swelling and disintegration of brain mitochondria, as well

Ž2q. w xas the reduction of brain membrane fluidity induced by Fe cysteine 94 . In vitroexperiments on mitochondria and membrane from ischemic and reperfusion brainindicate that both lignans significantly inhibited production of MDA and loss ofATPase activity induced by reoxygenation following anoxia. Oral administrationŽ .150 mgrkg of schisanhenol or schisandrin B induced increase of cytosol glu-tathione-peroxidase of brain in mice under the condition of reoxygenation fol-

w xlowing anoxia 94 .Human intellectual activity can be enhanced by S. chinensis so that work

Ž .efficiency is also increased. Schisandrin 5]10 mgrday, p.o. improved certainactivities requiring concentration, fine coordination, sensitivity and endurance, as


demonstrated in healthy young male adults in the following experiments: insertionof thread into needle within 5 min; error rate in telegraphist reception and

Ž .transmission; running marathon. S. chinensis seed powder 3 g daily, p.o. couldimprove vision, enlarge the visual field, improve hearing power, and increase the

w xdiscriminating ability of skin receptors 95 .

3.6. Pharmacokinetics and metabolism

Until now, there are no reports on the pharmacokinetics of S. chinensis extracts.After oral administration to healthy male subjects of 15 mg of schisandrin the

w xmean value of maximum plasma concentration was 96.1 " 14.1 ngrml 96 .Schisandrin was metabolised by rat liver microsomes to give three main first phasicmetabolites. Several oxidation routes appear to be involved: hydroxylation of analkyl substituent at first and then demethylation of the -OCH groups on the3

w xaromatic rings. The metabolites were found in urine and bile of rats 97 .After oral administration of 10 mgrkg to rats, the maximum serum concentra-

Ž .tion of gomisin A 1446.1 " 131.8 ngrml was reached at 15]30 min, over 80%w xbeing bound to serum proteins 98]100 . The rapid metabolisation of gomisin A,

w xhas been attributed to a first pass effect, producing demethylated metabolites 98w xand glucuronic and arylsulfate conjugates 101 .

After oral administration to rats of schisandrol A, this compound was absorbedfrom the gastrointestinal tract with a half-life of 58 min. After i.v. injection ofschisandrol A, the blood level showed a biphasic decline, with a half-life of theelimination phase of 42 min. Schisandrol A was detected in urine 1 h after oral

w xadministration 10 . Five minutes after i.v. administration, high levels of schisandrolA were found in the lungs, moderate amounts in the liver, heart, brain, and kidneysand low amounts in the ileum and spleen. In the brain, the higher amounts werefound in the hypothalamus, corpus striatum and hippocampus, and moderateamounts in the cerebral cortex and cerebellum. These differences may be relevant

w xto the neuroleptic and anticonvulsant properties of schisandrol A 102 .

3.7. Toxicology

Ž .The acute toxicity for S. chinensis fructus dried extract 4:1 , standardised to aŽ . w xconcentration of 2% of schisandrin was low LD ) 21 grkg, p.o. in rats 103 .50

Other authors reported the absence of lethal effects following intragastric adminis-w xtration of 5 grkg to mice 95 . The oral and i.p. LD values in mice for a50

Ž .petroleum ether extract of S. chinensis fruit 10% schisandrins were 10.5 and 4.4grkg, respectively. The oral LD of a petroleum ether extract standardised to 40%50

w xof schisandrins was 2.8 grkg in mice 93 .An ethanol extract of S. chinensis orally given to mice at doses of 0.6 and 1.2

grkg for 10 days resulted in only mild toxic effects, such as decrease in activity,piloerection and apathy, while body weight increase, blood picture and main organs

w xwere not significantly altered 95 .The p.o. toxicity of S. chinensis fructus dried extract standardised to a minimum


of 2% of schisandrins was studied in Landrace piglets for 90 days at daily doses of0.07, 0.36 and 0.72 grkg. The body weight and food intake, were not affectedduring the whole experimental period. No changes in the red blood cells, whiteblood cells, haemoglobin and hematocrit were found. The glycemia, urea andprotein concentrations did not show any significant variations with respect to thecontrol. Triglycerides, GOT and GGT were also not modified by S. chinensis

Žadministration. In the tissues examined liver, heart, kidneys, intestine, lungs,. w xspleen and gonads no toxic effect was observed 103 .

w xIn other studies 103 and using the same standardised dried extract of S.Ž .chinensis fruit 0.105]0.5 grkg per day, p.o. , the potential toxic effects on the

reproductive function was studied in rats and mice. No foetotoxicity in theseexperimental models was found. No changes in the implantation efficiency or otherinvestigated parameters were observed.

Information on the toxicity of S. chinensis lignans is very limited. With schisan-drin B, no death was observed following a single intragastric dose of 2 grkg to rats.Intragastric dosing of 200 mg for 30 days caused no significant effect on body

w xweight, haemoglobin and histology of the major organs in mice 95 . Schisandrin B,given intragastrically to dogs at 10 mgrkg daily for 4 weeks, did not affect appetite,body weight, blood picture, liver and kidney functions, as well as the histology of

w xthe liver 95 .

4. Conclusions

S. chinensis has been used in traditional Chinese medicine for thousands ofyears. In the last decades, the pharmacology and chemistry of this drug has beenextensively studied. Much evidence shows that S. chinensis and its dibenzocy-clootene lignans may act on the function of the liver. The findings are useful forfurther understanding the pharmacological basis of S. chinensis as an antioxidant,anticancer, tonic and antiaging drug. Furthermore, S. chinensis might also be usefulin the treatment of other diseases related to oxygen free radical injury andmetabolic disturbances, such as radiation injury, inflammations and reperfusion ofischemic organs, as well as in stress conditions and sport medicine.

Schisandra lignans seem also a potential source of new synthetic drugs, as is thew xcase of BDD 104,105 . Recently, halogenated gomisin J derivatives have been

Ž .shown to possess anti-human immunodeficiency virus HIV activities, by inhibitingthe activity of the enzyme reverse transcriptase as well as expressing cytoprotective

w xactivity in HIV-1-infected H9 cells. 106Nevertheless, despite the numerous pharmacological studies available, clinical

trials are necessary to support the use of S. chinensis in the medical practice.

Acknowledgements

This work was financed in part by a grant from the Swedish Herbal Institute,


Gothenburg, Sweden. The authors wish to thank Christina Gomzi for secretarialassistance.

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