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Submitted to:Dr. Afrasim MoinAsst ProfessorDept. Of PharmaceuticsJSSCP,mysore
Presented by:Rajendra Prasad.P.C
1st M.Pharm
Industrial Pharmacy
JSSCP, Mysore
Definition:-Bioactivation is defined as: Enzymatically
formed metabolites, which are more reactive than the
mother substance and excreted metabolites.
OR
Formation of highly reactive metabolites (from relatively
inert chemical compounds) which interact with the
tissues to precipitate one or more of the several forms
of toxicities such as carcinogenesis is called as
bioactivation or toxicological activation.
The most significant toxicological effects of
xenobiotics are reactive metabolites are:-
can react with nucleophilic sites
SH groups (glutathione, cysteine)
NH2 and – COOH groups (DNA, RNA, proteins)
Imbalance between formation and detoxification of reactive metabolites can arise from: enzyme induction (increased biotransformation and
formation of reactive metabolites)
high dose of xenobiotic
depletion of cellular defence mechanisms.
saturation of non-toxic pathways
Compounds Reactive pathway or intermediate product
Factors increasing toxicity
Acetaminophen N-hydroxylation Sulphate and GSH depletion
Acetyl hydrazine N-hydroxylation Aflatoxin B Epoxidation Further metabolism Benzene Epoxidation Benzo[a]pyrene Epoxidation PCB Epoxidation GSH depletion Tetrachlorcarbon Free radicals Reductive metabolism Halothane Free radicals Reductive metabolism Parathion Oxidation with
sulphur formation
Electrophiles
Free radicals
Electrophiles: - are species deficient in electron pair.
The enzyme system through which they generated is
cytochrome P-450. Carbon, nitrogen or sulphur
containing compounds can be metabolically activated to
yield electrophiles.
Important electrophiles are:Epoxides;-e.g., epoxide of benzo(a)pyrene present
in cigarette smoke which causes cancer.
Hydroxylamines, nitroso and azoxy derivatives, nitrenium ions and elemental sulphur.
Mechanism:- The mechanism by which electrophiles precipitate
toxicity is through covalent binding to nucleophilic tissue components such as macromolecules(proteins, nucleic acids, and lipids) or low molecular weight cellular constituents.
Covalent binding to DNA is responsible for
carcinogenicity and tumour formation.
The body’s defence against electrophiles is their
inactivation by conjugation with glutathione, the most
abundant cellular nucleophile with –SH group.
An e.g. of tissue toxicity due to electrophiles is
hepatotoxicity of paracetamol metabolites
Free radicals are species containing an odd number of electron. They may be positively charged (cation radical), negatively charged (anion radical) or neutral radical.R+ R- R
Cation radical Anion radical neutral radical
Free radicals are generally formed via NADPH cytochrome P-450 reductase or other flavincontaining reductases.
Xenobiotics that on metabolic activation yield free radicals are Quinone’s, aryl amines, nitro aryls and carbon tetrachloride.
Endogenous compounds such as epinephrine and DOPA can also generate free radicals.
Most free radicals are organic.They provide toxicity by peroxidation of cellular
components.
An important class of free radicals is inorganic free
radicals such as hydrogen peroxide and superoxide
anion.
These oxidative moieties can cause tremendous
tissue damage leading to mutations or cancer.
The potential toxicity of free radicals is far greater than
that of the electrophiles.
Cellular defence mechanisms against free radicals
include control imposed by membrane structure,
neutralization by glutathione, control exerted by non-
enzymatic antioxidant scavengers such as vitamin A,
E and C and enzymatic inactivation of oxygen derived
free radicals.
Generation of reactive metabolites is indicated by
modification in enzyme activities, formation of
glutathione conjugates and depletion in tissue levels
of glutathione. Since the availability of glutathione in
the body determines the threshold for toxic response,
thiols(e.g., N-acetyl cysteine) can be used to treat
poisoning by drugs such as paracetamol that yield
reactive metabolites.
Benzo(a)pyrene Aromatic epoxidation Lung cancer
Aflatoxin B1 Olefin epoxidation Hepatic cancer Thalidomide Hydrolytic cleavage of
lactam Teratogenesis
Chlorinated hydrocarbons
Oxidative dehalogenation
Nephrotoxicity
BIOPHARMACEUTICS AND
PHARMACOKINETICS BY
D.M.BRAHMANKAR,SUNIL B.JAISWAL.P.NO-
189-191
www.sciencedirect.com
Biopharmaceutics & Pharmacokinetics by Milo
Gibaldi, 4th edition
THANK YOU