SN7 SHORT NOTE 5M ★ High-yield

Describe the phases of biotransformation of xenobiotics with examples.

Biochemistry · 1st Professional — Pre-Clinical

Definition

Biotransformation (drug metabolism, detoxification) = the enzymatic conversion of lipid-soluble foreign compounds into water-soluble derivatives that can be excreted.

Xenobiotic = any compound foreign to the body — drugs, pollutants, food additives, plant toxins
The chief site is the liver; also intestine, lung, kidney and skin
Lipid-soluble compounds cannot be excreted by the kidney — they are reabsorbed. Increasing polarity is therefore the whole purpose

Phase I Reactions

Reaction	Enzyme	Example
Oxidation — the commonest	Cytochrome P450 (microsomal)	Hydroxylation, dealkylation, deamination
—	Non-microsomal — alcohol dehydrogenase, monoamine oxidase, xanthine oxidase	Ethanol, catecholamines
Reduction	Nitroreductase, azoreductase	Chloramphenicol, prontosil
Hydrolysis	Esterases, amidases	Aspirin, procaine, suxamethonium

Phase I introduces or exposes a functional group — –OH, –NH2, –SH, –COOH
The product may be more toxic than the parent — this is bioactivation

Phase II Reactions — Conjugation

Conjugation	Donor	Enzyme	Example
Glucuronidation — the commonest	UDP-glucuronic acid	UDP-glucuronyl transferase	Bilirubin, paracetamol, morphine, steroids
Sulphation	PAPS	Sulphotransferase	Steroids, paracetamol
Glutathione conjugation	Glutathione	Glutathione S-transferase	NAPQI, epoxides → mercapturic acid
Acetylation	Acetyl-CoA	N-acetyl transferase (NAT2)	Isoniazid, sulphonamides, hydralazine
Methylation	SAM	COMT, TPMT	Catecholamines, 6-mercaptopurine
Glycine conjugation	Glycine	Acyl-CoA glycine transferase	Benzoate → hippurate; bile acids

Phase II almost always detoxifies and always increases water solubility
Conjugation requires energy and a donor molecule, both of which can be depleted

CLINICAL PEARL

Toxicity arises when phase I outpaces phase II. In paracetamol overdose, conjugation is saturated, P450 keeps producing NAPQI, and once glutathione is exhausted the reactive metabolite attacks the hepatocyte. This is why an induced P450 and low glutathione — the alcoholic, the malnourished — make a standard overdose far more dangerous.

Factors Affecting Biotransformation

Age — neonates conjugate poorly (physiological jaundice, grey baby syndrome); the elderly metabolise more slowly
Genetics — slow and fast acetylators (NAT2); CYP2D6 and CYP2C19 polymorphisms; TPMT deficiency and azathioprine toxicity
Liver disease — reduced capacity; doses must be lowered
Nutrition — protein and glutathione depletion impair conjugation
Enzyme induction and inhibition by other drugs
Sex and pregnancy; disease states such as hypothyroidism

Applied Aspects

Prodrugs deliberately exploit phase I — codeine to morphine (CYP2D6), enalapril to enalaprilat, levodopa to dopamine. A poor metaboliser gets no analgesia from codeine
Slow acetylators are prone to isoniazid neuropathy and hepatitis, and to drug-induced lupus with hydralazine and procainamide — a common phenotype in India
Crigler–Najjar and Gilbert syndromes are inherited deficiencies of UDP-glucuronyl transferase, causing unconjugated hyperbilirubinaemia
First-pass metabolism in liver and gut wall determines oral bioavailability — the reason glyceryl trinitrate is given sublingually
Benzoate and phenylacetate are used therapeutically in urea cycle disorders, conjugating with glycine and glutamine to provide alternative routes of nitrogen excretion

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