Effects of lead on the induction of hepatic microsomal enzymes by phenobarbital and 3,4-benzpyrene.

Effects of Lead on the Induction of Hepatic Microsomal Enzymes by Phenobarbital and 3,4Benzpyrene. CHOW, C. P. AND CORNISH, H. H. (1978). Toxicol. Appl. Pharmacol. 43,219-228. A single ip injection of lead acetate (65 mg/kg) prolonged the duration of zoxazolamine paralysis in Sprague-Dawley rats and prevented the stimulation of zoxazolamine metabolism normally induced by phenobarbital. Lead also delayed the phenobarbital induction of hepatic microsomal cytochrome P-450 at 12 and 24 hr after treatment. However, the inhibitory effect of lead had disappeared and cytochrome P-450 concentrations were markedly elevated at 48 hr. Lead also diminished hepatic microsomal cytochrome P-448, normally resulting from benzyprene treatment. Neither lead, phenobarbital, benzyprene nor their combination had a significant effect on hepatic cytochrome b, values. Lead, in vitro, inhibited the hepatic microsomal NADPH<ytochrome c and P-450 reductase activity in a dose-dependent manner. In vivo, significant inhibition of NADPH-cytochrome c and P-450 reductase activity was observed after the injection of lead acetate. Significant inhibition coincides with the time when lead concentration in the hepatic microsomes was maximal. The inhibition of &aminolevulinic acid dehydratase (ALAD) activity at several blood lead concentrations was confirmed both in vivo and in vitro. This relationship between blood lead concentrations and ALAD activity was not altered by pretreatment with phenobarbital or bcnzpyrene.