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Lead intoxication: Effects on cytochrome P‐450‐mediated hepatic oxidations
Author(s) -
Alvares Alvito P.,
Fischbein Alf,
Sassa Shigeru,
Anderson Karl E.,
Kappas Attallah
Publication year - 1976
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt1976192183
Subject(s) - hexobarbital , chemistry , porphobilinogen , dehydratase , chelation therapy , microsome , excretion , medicine , pharmacology , ethylmorphine , endocrinology , cytochrome , toxicity , biochemistry , enzyme , chelation , organic chemistry
Acute administration of lead to rats caused significant decreases in cytochrome P‐450, ethylmorphine N‐demethylase, and aniline hydroxylase activities and prolonged hexobarbital‐induced sleeping times. However, chronic administration of lead to weanling rats caused no significant changes in hepatic cytochrome P‐450 levels or in the microsomal oxidative enzymes over a 12‐wk period. Eight patients exposed to lead in the process of burning through lead‐painted steel structures for at least 3 mo showed marked effects of chronic lead intoxication on the erythropoietic system: inhibition of erythrocyte δ‐aminolevulinic acid dehydratase, increased erythrocyte protoporphyrin levels, and increased urinary excretion of δ‐aminolevulinic acid. Chelation therapy greatly alleviated the inhibitory effects on dehydratase activity and decreased urinary δ‐aminolevulinic acid excretion. The plasma elimination rate of antipyrine, a drug primarily metabolized by hepatic microsomal enzymes, was determined in the 8 subjects prior to and following chelation therapy. In 7 of 8 subjects, chelation therapy shortened the antipyrine half‐lives, but the effect was minimal. These studies show that chronic lead exposure results in significant hematopoietic inhibition of the heme biosynthetic pathway without causing significant changes in hepatic cytochrome P‐450‐associated enzymic activities.