Spotlight on CYP4B1

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.

Automated summary

The mammalian cytochrome P450 monooxygenase CYP4B1 has the ability to activate a wide range of xenobiotics, leading to tissue-specific toxicities. It can also hydroxylate fatty acids and fatty alcohols. Recent crystal structures of native rabbit CYP4B1 and the p.E310A variant have provided insights into its enigmatic role in xenobiotic and endobiotic metabolism, as well as its unusual heme-binding characteristics. Although CYP4B1 does not play a major role in hepatic P450-catalyzed drug metabolism, its expression patterns have been associated with various cancers and potential roles in cancer development. This review will summarize the current research on CYP4B1, focusing on its roles in endogenous and exogenous compound metabolism, structural properties, cancer association, and potential application in targeted cancer therapy with suicide gene approaches.