Cytochrome P450 Enzymes as Drug Targets in Human Disease

Abstract

Although the mention of cytochrome P450 (P450) inhibition usually brings to mind unwanted variability in pharmacokinetics, in several cases P450s are good targets for inhibition. These P450s are essential, but in certain disease states, it is desirable to reduce the concentrations of their products. Most of the attention to date has been with human P450s 5A1, 11A1, 11B1, 11B2, 17A1, 19A1, and 51A1. In some of those cases, there are multiple drugs in use, e.g., exemestane, letrozole, and anastrozole with P450 19A1, the steroid aromatase target in breast cancer. There are also several targets that are less developed, e.g., P450s 2A6, 8B1, 4A11, 24A1, 26A1, and 26B1. SIGNIFICANCE STATEMENT: The selective inhibition of certain cytochrome P450s that have major physiological functions has been shown to be very efficacious in certain human diseases. In several cases, the search for better drugs continues.

Fig. 1.

P450 enzymes involved in major reactions of steroid metabolism.

Fig. 2.

Major P450 17A1 reactions: 17α-hydroxylation and 17α,20-lyase.

Fig. 3.

Abiraterone and two new candidates for P450 17A1 inhibition (BMS-737 and YXG-158).

Fig. 4.

P450 19A1 (aromatase) inhibitors.

Fig. 5.

X-ray crystal structure of Candida albicans P450 51A with bound posaconazole (Protein Data Bank 5FSA) (Hargrove et al., 2017). The drug is shown liganded to the iron in the (planar) heme (with the Cys-428 ligand below the plane of the porphyrin), and the arrow points to the extra hydroxyl group on the 3-pentyl side chain [compare posaconazole (SCH 56592) and SCH 51048] (Bennett et al., 2006; Nomeir et al., 2008).