Qualitative alteration in hepatic microsomal cytochrome P-450 apoproteins associated with bile duct ligation, and the administration of ethinyl estradiol, phenobarbital and 3-methylcholanthrene

Mackinnon, A.M.; Sutherland, E.; Simon, F.R.

Biochemical Pharmacology 27(1): 29-35

1978


ISSN/ISBN: 0006-2952
PMID: 619904
Accession: 006237066

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Abstract
Whether different forms of rat liver cytochrome P-450 are altered in hepatic disorders associated with impaired drug metabolism were examined. Total hepatic cytochrome P-450 is decreased after either bile duct ligation or the administration of ethinyl estradiol. Phenobarbital administered alone increases hepatic content of cytochrome P-450, and when administered with ethinyl estradiol the reduction in cytochrome P-450 was prevented. Microsomal ethylmorphine N-demethylase activities paralleled changes in cytochrome P-450 content, except in bile duct ligation, where it is diminished to a greater extent. Four forms of microsomal cytochrome P-450 apoproteins, ranging in MW from 50,000-58,000, were tentatively identified in a sodium dodecyl sulfate (SDS)-6 M urea polyacrylamide gel electrophoresis system by their responsiveness to pharmacological agents, turnover and benzidine peroxidase staining. Phenobarbital administration increased primarily band IV (50,000 daltons); in contrast only band III (53,000 daltons) was responsive to 3-methylcholanthene. Bile duct ligation was associated with a marked reduction in bands I, III and IV while bands I and III were decreased with ethinyl estradiol administration. Simultaneous administration of phenobarbital and ethinyl estradiol demonstrated return of band I and an increase in density of bands II and IV. The mechanism of this reversal by phenobarbital was determined by the double-isotope technique and demonstrates that phenobarbital increases the relative synthesis rates of P-450 apoproteins in ethinyl estradiol-treated rats. These studies support the hypothesis that multiple forms of cytochrome P-450 are present in liver microsomal membranes and that alterations in specific apoproteins may be associated with an increase in the functional properties of cytochrome P-450.