Effect of lead on hepatic delta-aminolaevulinic acid synthetase activity in the rat: a model for drug sensitivity in intermittent acute porphyria.
The hereditary hepatic porphyrias are disorders of porphyrin and haem synthesis characterized by a marked idiosyncrasy towards a variety of lipid soluble drugs. Most of these agents are inducers of the haemoprotein cytochrome P450, the terminal oxidase in drug metabolism. The primary genetic defect in intermittent acute porphyria is a partial deficiency of uroporphyrinogen I synthetase, which may result in a secondary derepression of delta-aminoaevulinic acid synthetase, the rate-limiting enzyme in the haem pathway. Analogous defects at more distant sites may explain the other hereditary hepatic porphyrias. As drug sensitivity may be related to the defect in haem synthesis, we investigated the effects of experimental partial blocks in haem synthesis produced by lead in rats. Drug effects on delta-aminolaevulinic acid synthetase, cytochrome P450, And drug metabolism were studied. Our findings indicate: a) While partial impairment of haem biosynthesis has only minor effects on delta-aminolaevulinic acid synthetase activity, it greatly enhances the sensitivity of delta-aminolaevulinic acid synthetase to induction by drugs and steroids, which when given alone, have little or no inducing effect on the enzyme. b) The experimental partial block in haem synthesis delays and impairs drug-mediated induction cytochrome P450 and drug metabolism in vitro. The findings may explain why a large number of structurally unrelated compounds with little effect on normal liver can precipitate "aucte porphyria".
D000624:5-Aminolevulinate Synthetase / Q000378:metabolism*; D000622:Aminolevulinic Acid / Q000652:urine; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004342:Drug Hypersensitivity / Q000201:enzymology* / Q000209:etiology; D004790:Enzyme Induction / Q000187:drug effects; D007854:Lead / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology*; D008297:Male; D010634:Phenobarbital / Q000494:pharmacology; D011164:Porphyrias / Q000139:chemically induced / Q000150:complications / Q000201:enzymology*; D051381:Rats
D007854:Lead; D000622:Aminolevulinic Acid; D003577:Cytochrome P-450 Enzyme System; D000624:5-Aminolevulinate Synthetase; D010634:Phenobarbital