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

Hideyuki Yamada, Hiromi Matsunaga, Kazuhiro Tsuji, Sanae Matsumoto, Midori Yamamoto, Yuji Ishii, Curtis J. Omiecinski, Kazuta Oguri

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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 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 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.

Original languageEnglish
Pages (from-to)986-993
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume295
Issue number3
Publication statusPublished - Dec 7 2000

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All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

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