Steroidogenic cytochrome P450 enzymes as drug target

Abstract

Human cytochrome P450 (CYP) enzymes are composed of 57 individual enzymes that perform monooxygenase activities. They have diverse physiological roles in metabolizing xenobiotics and producing important endogenous compounds, such as steroid hormones and vitamins. At least seven CYP enzymes are involved in steroid biosynthesis. Steroidogenesis primarily occurs in the adrenal glands and gonads, connecting each reaction to substrates and products. Steroids are essential for maintaining life and significantly contribute to sexual differentiation and reproductive functions within the body. Disorders in steroid biosynthesis can frequently cause serious health problems and lead to the development of diseases, such as prostate cancer, breast cancer, and Cushing's syndrome. In this review, we provide current updated knowledge on the major CYP enzymes involved in the biosynthetic process of steroids, with respect to their enzymatic mechanisms and clinical implications for the development of new drug candidates.

Keywords: CYP11A1; CYP11B1; CYP11B2; CYP17A1; CYP19A1; Cytochrome P450.

Fig. 1

Steroid biosynthesis pathway. FF-MAS (follicular fluid meiosis-activating sterol, 14-demethyl-14-dehydrolanosterol), DHEA (dehydroepiandrosterone), and DHT (dihydrotestosterone)

Fig. 2

Multistep oxidation reactions of cholesterol by CYP11A1

Fig. 3

Chemical structures of specific steroidogenic CYP inhibitors. CYP11A1 inhibitor, opevesostat; CYP17A1 inhibitor, abiraterone; CYP19A1 inhibitors, exemestane, letrozole, and anastrozole; CYP11B1 inhibitors, osilodrostat, and levoketoconazole; CYP11B2, baxdrostat and lorundrostat

Fig. 4

Structural views of inhibitor binding in the active sites of steroidogenic CYP enzymes. a Binding of cholesterol to CYP11A1, b binding of abiraterone to CYP17A1, c binding of exemestane to CYP19A1

Fig. 5

Sequential enzyme reactions to produce estrogens by CYP19A