Emerging data from new research suggests that abnormally elevated CYP24 expression contributes to the pathology of certain diseases including chronic kidney disease (CKD), cancers, and psoriasis.
CYP24, a member of the cytochrome P450 enzyme superfamily, is the key enzyme involved in vitamin D catabolism. Increased levels of CYP24 decrease the effectiveness of vitamin D replacement therapies and potentially contribute to local or systemic vitamin D insufficiency. Specific inhibition of CYP24 provides a new approach to treating diseases responsive to vitamin D therapy.
Enzymes belonging to the cytochrome P450 superfamily catalyze critical biochemical reactions in the body including hydroxylations, epoxidations, oxygenations, and dehalogenations, which are needed to activate or inactivate endogenous-signaling ligands and detoxify xenobiotic compounds such as drugs. Those P450s exclusively involved in the metabolism of endogenous ligands such as fat-soluble vitamins (vitamins A and D), fatty acids, steroids, eicosanoids, and bile acids have attracted interest as potential drug targets because they play pivotal roles in modulating tissue responses to these substances and their synthetic counterparts.
A number of P450 inhibitors have been developed that utilize functional azole groups to target the heme moiety at the enzyme’s catalytic core. Because heme resides at the core of all P450s, such inhibitors lack specificity and, consequently, can block activity of drug-metabolizing P450s, thus predisposing patients to possible drug-drug interactions (Figure 1). New vitamin D compounds targeting the CYP24 substrate binding pocket, rather than the catalytic site, allow much more potent inhibition with higher specificity.