Abstract

The Qdj:Sprague-Dawley (SD) rat is a mutant strain lacking in phenobarbital (PB)-mediated induction of CYP2B2. The presence of interindividual differences in the hepatic content of CYP2B proteins and testosterone 16β-hydroxylase activity demonstrated that the breeding colony of Qdj:SD rats involves normal (+/+) and intermediate (+/−) phenotypes as well as mutant (−/−)-type rats. Although PB-treated Qdj:SD (−/−) rats expressed CYP2B1 normally, testosterone 16β-hydroxylase activity in these rats was quite low. Analysis of regioselective metabolism of testosterone and 4-hydroxybiphenyl glucuronidation demonstrated normal catalytic activities associated with other forms of cytochrome P450s, including CYP2A, -2C, and -3A, as well as PB-inducible UDP-glucuronosyltransferase in Qdj:SD (−/−) rats. There were no serious mutations in the exons of theCYP2B1 gene in Qdj:SD (−/−) rats, demonstrating that this gene codes a functional CYP2B1. These observations suggest that CYP2B1 needs the interaction with CYP2B2 to exert the full function. The CYP2B2 gene in Qdj:SD (−/−) rats was the same as that in wild-type (+/+) rats in its length of the region containing all exon/introns and 5′-upstream up to −2.3 kilobase pairs. Malignant mutation such as stop codon formation was not observed in the exons, and no mutation was detected in the region containing the PB-responsive unit. These results strongly suggest that impaired induction of CYP2B2 in Qdj:SD (−/−) rats is attributable either to mutation at the region different from PB-responsive unit and exons or to absence or lowered expression of trans-acting factor(s) necessary for gene regulation.