Spotlight on CYP4B1

Abstract

The mammalian cytochrome P450 monooxygenase CYP4B1 can bioactivate a wide range of xenobiotics, such as its defining/hallmark substrate 4-ipomeanol leading to tissue-specific toxicities. Similar to other members of the CYP4 family, CYP4B1 has the ability to hydroxylate fatty acids and fatty alcohols. Structural insights into the enigmatic role of CYP4B1 with functions in both, xenobiotic and endobiotic metabolism, as well as its unusual heme-binding characteristics are now possible by the recently solved crystal structures of native rabbit CYP4B1 and the p.E310A variant. Importantly, CYP4B1 does not play a major role in hepatic P450-catalyzed phase I drug metabolism due to its predominant extra-hepatic expression, mainly in the lung. In addition, no catalytic activity of human CYP4B1 has been observed owing to a unique substitution of an evolutionary strongly conserved proline 427 to serine. Nevertheless, association of CYP4B1 expression patterns with various cancers and potential roles in cancer development have been reported for the human enzyme. This review will summarize the current status of CYP4B1 research with a spotlight on its roles in the metabolism of endogenous and exogenous compounds, structural properties, and cancer association, as well as its potential application in suicide gene approaches for targeted cancer therapy.

Keywords: CYP4B1; bioactivation; cancer; cytochrome P450; drug metabolism; endobiotic metabolism; structure; suicide gene; xenobiotics.

Figure 1

Overview of CYP4B1 substrates. (a) Endogenous substrates that are hydroxylated by CYP4B1 include fatty acids 1–11, 20, fatty alcohols 12–15, and n-alkanes 16–19. (b) Exogenous substrates of CYP4B1 can be grouped into cyclic amines 21–23, VPA 24, and furyl-containing compounds 25–38. (c) Schematic representation of the bioactivation pathway of 3-furyl-containing compounds 25, 26, 31–38. CYP4B1 catalyzes the epoxidation of the furan ring, followed by non-enzymatic rearrangement to an enedial intermediate. In vivo, these reactive enedial intermediates bind to macromolecules (e.g., proteins) causing cytotoxicity; in vitro, they can be trapped by reactions with nitrogen and sulfur nucleophiles (e.g., NAC/NAL) that generate stable S-substituted pyrroles.

Figure 2

(a) Sequence and structure comparison between native rCYP4B1 (cyan) and the homology model of native hCYP4B1 (mauve): Location of S427 of hCYP4B1 is highlighted (b) Homology model of engineered h-P+12: Nonidentical amino acids compared to native hCYP4B1 are depicted (green: hydrophilic, grey: hydrophobic, red: negatively charged, blue: positively charged). Please note that the engineered h-P+12 does not contain parts of the original N-terminus (first α-helix).

Figure 3

Schematic representation of a CYP4B1-based suicide gene system. CYP4B1-deficient cells are transduced with integrating viral vectors to express an active CYP4B1 protein. This enzyme converts a non-toxic substance (protoxin) into a cellular toxin only in CYP4B1-positive cells.