A pleiotropic response to phenobarbital-type enzyme inducers in the F344/NCr rat. Effects of chemicals of varied structure

Biochem Pharmacol. 1992 Mar 3;43(5):1067-78. doi: 10.1016/0006-2952(92)90614-o.


The effects of a number of phenobarbital-type inducers on selected drug-metabolizing enzymes in male F344/NCr rats were determined by measuring specific catalytic activities and/or by measuring the levels of RNA which hybridize with specific probes for the corresponding genes. The effects on hepatic CYP2B1 were assessed by measuring the levels of CYP2B1-specific RNA and benzyloxyresorufin O-dealkylase and testosterone 16 beta-hydroxylase activities. Levels of CYP3A were monitored by measuring the rate of hydroxylation of testosterone at the 6 beta-position. Microsomal epoxide hydrolase activity was determined by measurement of cellular RNA specific for this form and by assaying the hydrolysis of benzo[a]pyrene-4,5-oxide. UDP-glucuronyltransferase activity was assayed by measuring the glucuronidation of 3-hydroxybenz[a]anthracene. Levels of glutathione S-transferase Ya/Yc were measured by quantifying total cellular RNA coding for the proteins. When male F344/NCr rats were administered various doses of phenobarbital or dichlorodiphenyltrichloroethane (DDT), strong correlations between the induction of CYP2B1 and the induction of epoxide hydrolase or UDP-glucuronyltransferase activities were observed. Treatment of rats with barbiturates, hydantoins, halogenated pesticides such as DDT or alpha-hexachlorocyclohexane, 2,4,5,2',4',5'-hexachlorobiphenyl, CYP2B1 inhibitors such as clotrimazole or clonazepam, or such structurally-diverse compounds as 2-hexanone or diallyl sulfide resulted in induction of CYP2B1-mediated enzyme activity and induction of certain other forms of cytochrome P450, microsomal epoxide hydrolase, at least one form of UDP-glucuronyltransferase, and multiple forms of glutathione S-transferase. This suggests that, as a class, compounds which induce CYP2B1 also induce a coordinate hepatic pleiotropic response which includes induction of these other phase I and phase II drug-metabolizing enzymes.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Aryl Hydrocarbon Hydroxylases*
  • Base Sequence
  • Cytochrome P-450 CYP1A1
  • Cytochrome P-450 Enzyme System / biosynthesis*
  • Cytochrome P-450 Enzyme System / genetics
  • DDT / pharmacology*
  • Enzyme Induction / drug effects
  • Epoxide Hydrolases / biosynthesis
  • Glucuronosyltransferase / biosynthesis*
  • Glutathione Transferase / biosynthesis*
  • Liver / drug effects
  • Liver / enzymology
  • Male
  • Molecular Sequence Data
  • Oligonucleotide Probes
  • Oxidoreductases / biosynthesis
  • Phenobarbital / pharmacology*
  • RNA / biosynthesis
  • Rats
  • Rats, Inbred F344
  • Steroid Hydroxylases / biosynthesis
  • Xenobiotics / pharmacology


  • Oligonucleotide Probes
  • Xenobiotics
  • RNA
  • Cytochrome P-450 Enzyme System
  • DDT
  • Oxidoreductases
  • Steroid Hydroxylases
  • Aryl Hydrocarbon Hydroxylases
  • Cytochrome P-450 CYP1A1
  • testosterone 7-alpha-hydroxylase, hamster
  • Glucuronosyltransferase
  • Glutathione Transferase
  • Epoxide Hydrolases
  • Phenobarbital