Intersection of the Roles of Cytochrome P450 Enzymes with Xenobiotic and Endogenous Substrates: Relevance to Toxicity and Drug Interactions

Abstract

Today much is known about cytochrome P450 (P450) enzymes and their catalytic specificity, but the range of reactions catalyzed by each still continues to surprise. Historically, P450s had been considered to be involved in either the metabolism of xenobiotics or endogenous chemicals, in the former case playing a generally protective role and in the latter case a defined physiological role. However, the line of demarcation is sometimes blurred. It is difficult to be completely specific in drug design, and some P450s involved in the metabolism of steroids and vitamins can be off-targets. In a number of cases, drugs have been developed that act on some of those P450s as primary targets, e.g., steroid aromatase inhibitors. Several of the P450s involved in the metabolism of endogenous substrates are less specific than once thought and oxidize several related structures. Some of the P450s that primarily oxidize endogenous chemicals have been shown to oxidize xenobiotic chemicals, even in a bioactivation mode.

Figure 1

Oxidations of lathosterol and 7-dehydrocholesterol by P450 7A1. (A) Lathosterol; (B) 7-dehydrocholesterol. The a and b pathways indicate hydride transfer and closure to an epoxide, respectively.

Figure 2

Multiple oxidations catalyzed by P450 17A1. Sites of oxidation are indicted in red. The site of oxidation in the structure in the lower right corner has not been ascertained.

Figure 3

Multiple oxidations of sterols catalyzed by P450 46A1.^, Sites of oxidation are indicted in red. Sterol numbering is shown in the structure of cholesterol (upper left structure). The oxidations with 7-dehydrocholesterol had not been detected in a previous study, presumably due to limited sensitivity.

Figure 4

Multiple oxidations of non-sterol compounds catalyzed by P450 46A1.

Figure 5

Human P450 27A1 and carfilzomib. (A) Structure of carfilzomib and acetylenic analog (OP-829). (B) Inhibition of P450 27A1 by carfilzomib with (filled circles) and without (filled squares) preincubation (60 min at 37 °C, no cofactors present). IC₅₀ with pre-incubation: 1.3 ± 0.1 μM; IC₅₀ without pre-incubation: 1.1 ± 0.1 μM.

Figure 6

Activation of “BMS A” by P450 11A1. The site of the ¹⁴C label is indicated by an asterisk (*). Proposed reactive products are indicated in brackets.