1. METABOLISM /
BIOTRANSFORMATION
of TOXICANTS

2. Objectives
PHASE II REACTIONS.
FACTORS AFFECTING METABOLISM.

3. PHASE 2 Reactions CONJUGATIONS
-OH, -SH, -COOH, -CONH with glucuronic acid to give glucuronides
-OH with sulphate to give sulphates
-NH2, -CONH2, amino acids, sulpha drugs with acetyl- to give acetylated derivatives
-halo, -nitrate, epoxide, sulphate with glutathione to give glutathione conjugates
all tend to be less lipid soluble and therefore better excreted (less well reabsorbed)

4. Cofactors for Phase II
W. Tassaneeyakul
(Source: Parkinson 2001)

5. BIOACTIVATIONS
(Source: Parkinson 2001)

6. (Source: Parkinson 2001)

7. Factors Affecting Metabolism
Age (reduced in aged & children)
Sex (women more sensitive to ethanol)
Species (phenylbutazone (NSAIDs) 3h rabbit, 6h horse, 8h monkey, 18h mouse, 36h man)
Race (fast and slow isoniazid acetylators, fast = 95% Eskimo, 50% Brits, 13% Finns 13% Egyptians)
Clinical or physiological conditions

8. AGE Birth Adult % Enzyme activity Fetus & Neonate :
Lower drug metabolizing capacity compare to adult
Sensitive to drug,
Long duration of action
Glucoronosyltransferase (UDPGT)
GREY BABY SYNDROME (toxicity of chloramphenicol in newborn baby)
Vomiting
irregular & rapid respiration
Cyanosis
% Enzyme activity
Birth
Adult

9. SPECIES Rate of Hexobarbital metabolism
Coumarin : 7-Hydroxylation found in only human, rabbit, cat but not in rat, mice
Therefore animal used for toxicity test must has the drug metabolism process similar to human

10. GENETICS
Activity of xenobiotic metabolizing enzymes can be vary between individual
Population can be divided to RAPID METABOLIZER and SLOW METABOLIZERS
Variation in toxicant metabolism
Variation of toxicant level in the body
Variation of toxicant response/toxicity

11. DISEASES Liver diseases : reduced drug metabolism cirrhosis
Acute alcohol exposure: chronic ethanol exposure, alcoholic cirrhosis
Endocrine disorders : diabetes

12. FOOD Nutrients Non-nutrients Pyrolysis products Protein
Cabohydrate
Fat
Vitamins
Non-nutrients
Pyrolysis products
some chemical in plants : Indole compounds (Cabbage/ Brussel sprout)
PYROLYSIS PRODUCTS
Break down products of amino acid after over cook meat at high temp (fried/charcoal -broiled)
Induce drug metabolizing enzymes : P450s and UDPGT
Mutagenicity/ Carcinogenicity

13. Chemicals/ Drugs INHIBITORS cimetidine
prolongs action of toxicants or inhibits action of those biotransformed to active agents (pro-drugs)
INDUCERS barbiturates, carbamazepine
shorten action of toxicants or increase effects of those biotransformed to active agents