Bioactivity of Curcumin on the Cytochrome P450 Enzymes of the Steroidogenic Pathway

Abstract

Turmeric, a popular ingredient in the cuisine of many Asian countries, comes from the roots of the Curcuma longa and is known for its use in Chinese and Ayurvedic medicine. Turmeric is rich in curcuminoids, including curcumin, demethoxycurcumin, and bisdemethoxycurcumin. Curcuminoids have potent wound healing, anti-inflammatory, and anti-carcinogenic activities. While curcuminoids have been studied for many years, not much is known about their effects on steroid metabolism. Since many anti-cancer drugs target enzymes from the steroidogenic pathway, we tested the effect of curcuminoids on cytochrome P450 CYP17A1, CYP21A2, and CYP19A1 enzyme activities. When using 10 µg/mL of curcuminoids, both the 17α-hydroxylase as well as 17,20 lyase activities of CYP17A1 were reduced significantly. On the other hand, only a mild reduction in CYP21A2 activity was observed. Furthermore, CYP19A1 activity was also reduced up to ~20% of control when using 1–100 µg/mL of curcuminoids in a dose-dependent manner. Molecular docking studies confirmed that curcumin could dock onto the active sites of CYP17A1, CYP19A1, as well as CYP21A2. In CYP17A1 and CYP19A1, curcumin docked within 2.5 Å of central heme while in CYP21A2 the distance from heme was 3.4 Å, which is still in the same range or lower than distances of bound steroid substrates. These studies suggest that curcuminoids may cause inhibition of steroid metabolism, especially at higher dosages. Also, the recent popularity of turmeric powder as a dilatory supplement needs further evaluation for the effect of curcuminoids on steroid metabolism. The molecular structure of curcuminoids could be modified to generate better lead compounds with inhibitory effects on CYP17A1 and CYP19A1 for potential drugs against prostate cancer and breast cancer.

Effects of Curcumin on Glycemic Control and Lipid Profile in Polycystic Ovary Syndrome: Systematic Review with Meta-Analysis and Trial Sequential Analysis

“…This observation is likely attributed to the downregulation of the activity of cytochrome P450c17. Curcumin has been demonstrated to reduce the activity of cytochrome P450c17 in a dose-dependent manner in vitro [ 63 ]. In an animal model, the expression of cytochrome P450c17 in the ovaries of the curcumin-treated mice is reduced to the same level as in those of the wild-type ones [ 64 ].…”

Identifying the Antitumor Effects of Curcumin on Lung Adenocarcinoma Using Comprehensive Bioinformatics Analysis

“…It has been shown that curcumin could bind to the active sites of steroid metabolizing P450s and the inhibition of CYP17A1 and CYP19A1 provides a template for structural modifications to produce effective and safe compounds to inhibit the growth of prostate cancer as well as breast cancer. 49 However, there are still lack of studies on curcumin evaluating the inhibitory effects on cytochrome P450 and thus as an anti-lung cancer agent, which provides a direction for future research. Curcumin has been reported to inhibit the invasion and metastasis of many cancer cells, including lung cancer, by upregulating the expression of E-cadherin.…”

Loss of Protein Stability and Function Caused by P228L Variation in NADPH-Cytochrome P450 Reductase Linked to Lower Testosterone Levels

“…Activities of CYP17A1 and CYP19A1 were measured with WT or the P228L variant of POR using methods described in detail in our previous publications [ 14 , 18 , 20 , 21 , 30 , 40 , 44 , 45 ].…”