CYP17A1 inhibitor abiraterone, an anti-prostate cancer drug, also inhibits the 21-hydroxylase activity of CYP21A2

Abstract

Abiraterone is an inhibitor of CYP17A1 which is used for the treatment of castration resistant prostate cancer. Abiraterone is known to inhibit several drug metabolizing cytochrome P450 enzymes including CYP1A2, CYP2D6, CYP2C8, CYP2C9, CYP2C19, CYP3A4 and CYP3A5, but its effects on steroid metabolizing P450 enzymes are not clear. In preliminary results, we had observed inhibition of CYP21A2 by 1μM abiraterone. Here we are reporting the effect of abiraterone on activities of CYP21A2 in human adrenal cells as well as with purified recombinant CYP21A2. Cells were treated with varying concentrations of abiraterone for 24h and CYP21A2 activity was measured using [H] 17-hydroxyprogesterone as substrate. Whole steroid profile changes were determined by gas chromatography-mass spectrometry. Binding of abiraterone to purified CYP21A2 protein was measured spectroscopically. Computational docking was used to study the binding and interaction of abiraterone with CYP21A2. Abiraterone caused significant reduction in CYP21A2 activity in assays with cells and an inhibition of CYP21A2 activity was also observed in experiments using recombinant purified proteins. Abiraterone binds to CYP21A2 with an estimated Kd of 6.3μM. These inhibitory effects of abiraterone are at clinically used concentrations. A loss of CYP21A2 activity in combination with reduction of CYP17A1 activities by abiraterone could result in lower cortisol levels and may require monitoring for any potential adverse effects.

Bioactivity of curcumin on the cytochrome P450 enzymes of the steroidogenic pathway

“…At 10 µg/ml concentration of curcuminoids the activity of CYP21A2 was only moderately reduced compared to control, and was less than the effects observed for inhibition of CYP171 and CYP19A1 activities. The anti-prostate-cancer drug abiraterone also inhibited the CYP21A2 activity as we have shown previously [20,21].…”

“…lyase activity has been linked to polycystic ovary syndrome. CYP17A1 is also a metabolic target for chemotherapy of castration-resistant prostate cancer [20,44]. Novel compounds that are safe and non-toxic are needed to target CYP17A1 and CYP19A1 activities to treat metabolic disorders resulting from excess production of androgens or estrogens.…”

“…Only a minor effect on CYP21A2 activity by curcuminoids compared to inhibition of CYP17A1 (50% inhibition of 17,20 lyase activity at 5 µg/ml compared to no significant effect on CYP21A2 activity at the same concentration) was observed. This suggests that compounds based on curcuminoids may be better and safer inhibitors for use in hyperandrogenic states like polycystic ovary syndrome, especially in children and young adults, and avoid the toxic effects of abiraterone which severely inhibits CYP21A2 activity [20,21].…”

“…The CYP17A1 enzyme (GeneID: 1586, 10q24.32, GRCh38 chr10:102,830,531-102,837,533, NCBI: NM_000102.4 , NP_000093.1, OMIM: 609300) regulates sex steroid biosynthesis in humans through 17α-hydroxylase/17,20 lyase activities and is a target of anti-prostate cancer drug abiraterone [19][20][21]. Aromatase (CYP19A1) converts androstenedione and testosterone into estrogens and is a target for the treatment for breast cancer [22][23][24].…”

Differential effects of variations in human P450 oxidoreductase on the aromatase activity of CYP19A1 polymorphisms R264C and R264H

“…Two different types of the cytochrome P450 family of proteins are present in humans [5]. The P450 type 1 proteins are found in the mitochondrion and are responsible for the metabolism of steroid hormones and sterols and are targets for drugs in a range of disorders [6][7][8][9][10][11]. The P450 type 2 proteins are localized in the endoplasmic reticulum and have a range of metabolic activities, including drugs, xenobiotics as well as endogenous substrates, and steroid hormones like progesterone, dehydroepiandrosterone, and testosterone [12][13][14][15][16][17].…”