Sequence analyses of CYP2B genes and catalytic profiles for p450s in Qdj: Sprague-Dawley rats that lack response to the phenobarbital-mediated induction of CYP2B2

The Qdj:Sprague-Dawley (SD) rat is a mutant strain lacking in phenobarbital (PB)-mediated induction of CYP2B2. The presence of interindividual differe nces in the hepatic content of CYP2B proteins and testosterone 16 beta -hyd roxylase activity demonstrated that the breeding colony of Qdj: SD rats inv olves normal (+/+) and intermediate (+/-) phenotypes as well as mutant (-/- )-type rats. Although PB-treated Qdj: SD (-/-) rats expressed CYP2B1 normal ly, testosterone 16 beta -hydroxylase activity in these rats was quite low. Analysis of regioselective metabolism of testosterone and 4-hydroxybipheny l 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 the CYP2B1 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 fun ction. The CYP2B2 gene in Qdj: SD (-/-) rats was the same as that in wild-t ype (+/+) 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 codo n formation was not observed in the exons, and no mutation was detected in the region containing the PB-responsive unit. These results strongly sugges t that impaired induction of CYP2B2 in Qdj: SD (-/-) rats is attributable e ither to mutation at the region different from PB-responsive unit and exons or to absence or lowered expression of trans-acting factor(s) necessary fo r gene regulation.