Differing Amino Acid Residues are Critical for Differences in Phenylimidazole-Induced Inhibition of Cytochrome P450s
James Halpert University of Texas Medical Branch R01ES03619 and P30ES06676
Background: Cytochrome P450 is a family of powerful detoxification enzymes. Over 60 key forms are known, with hundreds of genetic variations possible, producing a wide variety of susceptibilities to specific toxins. A single P450 may be solely or primarily responsible for the detoxification or activation of a specific compound. Therefore, the amounts of specific P450s expressed in organs of individual humans or experimental animals can determine the metabolism and pharmacological activity or toxicity of a specific drug or compound. Predicting the specificities of P450s is a major challenge to the drug discovery process. Identifying inhibitors of specific P450s is crucial for discovering those that are involved in the biotransformation of drugs. Understanding the molecular basis for P450 inhibition aides drug development by suggesting structural alterations that help to minimize drug-drug interactions.
Advance: Previous work identified a class of compunds known as phenylimidazoles as potent P450 inhibitors. The current study reports that rabbit cytochromes P4502B4 and 2B5 and rat 2B1 (CYP2B4, CYP2B5, and CYP2B1) are differentially inhibited by 4-phenylimidazole. The differences in inhibition are as much as 32 fold. Four specific amino acid residues were identified as critical to these differences. When amino acid substitution was carried out at these 4 sites, the inhibition was partially reversed.
Implication: The main conclusion drawn from this study is that differences in inhibition are not only because of single residue mismatches, but also by interactions between residues. These findings will contribute to better understanding of CYP2B enzymes, may aid in the design of select P450 inhibitors, and will help in the development of drugs that avoid drug interactions due to P450 inhibition.
Citation: Spatzenegger M, Wang Q, He YQ, Wester MR, Johnson EF, Halpert JR. Amino acid residues critical for differential inhibition of CYP2B4, CYP2B5, and CYP2B1 by phenylimidazoles. Mol Pharmacol. 2001 Mar;59(3):475-84.