Metabolism & Toxicity

MetabolismEnvironmental

Genetic Variations

the rate of alcohol drinking

the presence of food in the stomach

the type of alcoholic beverage (Beer/Rum/Whisky)

genetic factors (variations in the principal alcohol-metabolizing enzymes)

Blood Alcohol Concentration (BAC)Decides the effects of Alcohol on various tissues.

BACDepends

on

Stomach 20%Small Intestine 80%

First pass metabolism

Elimination rate: 15mg/dl/hr

The alcohol elimination rate varies widely (i.e., three-fold) among individuals.

Bennion and Li 1976; Kopun and Propping 1977

Influenced by factors:chronic alcohol consumption

diet age

Smoking .

Interactions with metabolic pathways

Elimination of Alcohol & Toxic Metabolites

Alcohol Dehydogenase

(Cytosol)

AldehydeDehydrogenase (Mitochondria) Cytochrome P450

(Microsomes)

Catalase(Peroxisomes)

Samir Zakhari, Alcohol Research & Health, 2009

Acetaldehyde

Protein Adducts

DNA Adducts

Neuro-transmitter

Adducts

Salsolinol

1-N2, Propane deoxy guanosine

Acetate: Acetyl CoA – Lipid & Cholesterol

Biosynthesis Increase blood flow to liver.

Increased NADH/NAD+ ratio

• Hypoxic state in the cell – Lactic Acidosis

• Highly reduced cytosolic environment.

• Hypoglycemia – Due to inhibition of Gluconeogenesis.

ADH & ALDH involved in Retinol & Retinoic Acid Metabolism.

Fetal Alcohol Syndrome.

www.medicalbiochemistrypage.org

Liver damage,Hepatocellular Carcinoma

Fetal Alcohol Syndrome

Microsomal Ethanol Oxidizing System (MEOS)

 PORTER:Drinking turns your nose red (Vasodilatation), it puts you to sleep (CNS depression), and it makes you urinate (Inhibits secretion of Vasopressin). Sir, it provokes and unprovokes. It provokes the desire, but it takes away the performance. It persuades you and discourages you.  

Shakespeare, Macbeth, Act 2, Scene 2

MACDUFF:What three things does drink make a man do?

Acute Alcohol Intoxication:

80mg/dl: Slurred speech, incoordination, Unsteady gait.

80 -200mg/dl: Cognitive effects, Aggressiveness, Amnesia.

>200mg/dl: Nystagmus, Coma, Death.

Legal limits: 30mg/100mL.

Genetic Variations:ADH1B2: Jews

ADH1B3: African AmericansFaster Metabolism.- Elevated Aldehyde levels- Reduced

Alcohol intake.Indians: ADH1B1. No ADH1B3

ALDH2*2: Elevated Aldehyde Levels- Reduced Alcohol Intake.

Methanol

Country Liquor (Arrack, Hooch, Bootleg)

Paint Thinner

Anti freeze in Automobiles

Laboratory chemical

Food contaminants

Methanol

Toxic Dose: 20mg/dl.Lethal Dose : 300-1000mg/dl

Methanol

Optic Nerve Injury

Ocular Toxicity &

Death

Metabolic Acidosis

Methanol Poisoning

Poison Information Monograph, WHO, 2007

Treatment of Methanol Poisoning

Maintenance of Airway, Breathing, Circulation.

I.V., Sodium Bicarbonate for acidosis.

Ethanol i.v., - a competitive inhibitor of Alcohol Dehydrogenase.

4- Methyl Pyrazole – a competitive inhibitor of Alcohol Dehydrogenase.

Folate to metabolize and eliminate Formic acid.

Hemodialysis.

Further Reading:

• Goodman & Gilman, The Pharmacological Basis of Therapeutics, edn 12th.

• Overview: How is Alcohol metabolized by the body?- Samir Zakhari, Alcohol Research and Health.

Thank you