Effect of Essential Oil Components on the Activity of Steroidogenic Cytochrome P450.

Endocrine-disrupting chemicals (EDCs) may impact the development of prostate cancer (PCa) by altering the steroid metabolism. Although their exact mechanism of action in controlling tumor growth is not known, EDCs may inhibit steroidogenic enzymes such as CYP17A1 or CYP19A1 which are involved in the production of androgens or estrogens. High levels of circulating androgens are linked to PCa in men and Polycystic Ovary Syndrome (PCOS) in women. Essential oils or their metabolites, like lavender oil and tea tree oil, have been reported to act as potential EDCs and contribute towards sex steroid imbalance in cases of prepubertal gynecomastia in boys and premature thelarche in girls due to the exposure to lavender-based fragrances. We screened a range of EO components to determine their effects on CYP17A1 and CYP19A1. Computational docking was performed to predict the binding of essential oils with CYP17A1 and CYP19A1. Functional assays were performed using the radiolabeled substrates or Liquid Chromatography-High-Resolution Mass Spectrometry and cell viability assays were carried out in LNCaP cells. Many of the tested compounds bind close to the active site of CYP17A1, and (+)-Cedrol had the best binding with CYP17A1 and CYP19A1. Eucalyptol, Dihydro-ß-Ionone, and (-)-α-pinene showed 20% to 40% inhibition of dehydroepiandrosterone production; and some compounds also effected CYP19A1. Extensive use of these essential oils in various beauty and hygiene products is common, but only limited knowledge about their potential detrimental side effects exists. Our results suggest that prolonged exposure to some of these essential oils may result in steroid imbalances. On the other hand, due to their effect on lowering androgen output and ability to bind at the active site of steroidogenic cytochrome P450s, these compounds may provide design ideas for novel compounds against hyperandrogenic disorders such as PCa and PCOS.

Exploring the Potential of Sulfur Moieties in Compounds Inhibiting Steroidogenesis.

This study reports on the synthesis and evaluation of novel compounds replacing the nitrogen-containing heterocyclic ring on the chemical backbone structure of cytochrome P450 17α-hydroxylase/12,20-lyase (CYP17A1) inhibitors with a phenyl bearing a sulfur-based substituent. Initial screening revealed compounds with marked inhibition of CYP17A1 activity. The selectivity of compounds was thereafter determined against cytochrome P450 21-hydroxylase, cytochrome P450 3A4, and cytochrome P450 oxidoreductase. Additionally, the compounds showed weak inhibitory activity against aldo-keto reductase 1C3 (AKR1C3). The compounds' impact on steroid hormone levels was also assessed, with some notable modulatory effects observed. This work paves the way for developing more potent dual inhibitors specifically targeting CYP17A1 and AKR1C3.

Non-steroidal CYP17A1 Inhibitors: Discovery and Assessment.

CYP17A1 is an enzyme that plays a major role in steroidogenesis and is critically involved in the biosynthesis of steroid hormones. Therefore, it remains an attractive target in several serious hormone-dependent cancer diseases, such as prostate cancer and breast cancer. The medicinal chemistry community has been committed to the discovery and development of CYP17A1 inhibitors for many years, particularly for the treatment of castration-resistant prostate cancer. The current Perspective reflects upon the discovery and evaluation of non-steroidal CYP17A1 inhibitors from a medicinal chemistry angle. Emphasis is placed on the structural aspects of the target, key learnings from the presented chemotypes, and design guidelines for future inhibitors.

Wound Management Property of a Hydroethanolic Leaf Extract of Cnestis ferruginea DC.

OBJECTIVE: To establish the wound management property of a hydroethanolic Cnestis ferruginea leaf extract (CFHE). MATERIALS AND METHODS: The wound area was measured after excision at the dorsal part of the Albino rats, and after treatment with 5-15% w/w CFHE ointments for 14 days. Absorbances of platelet-rich plasma treated with 0.8-100 mg/mL CFHE and an aggregating agent were spectrophotometrically determined in an in vitro platelet aggregation test. Wound tissue histopathology of CFHE ointment-treated animals revealed angiogenesis, reepithelialization, deposition of collagen, and granular tissue formation in wound tissues. Reduction in thigh oedema and pain threshold, in 7-day-old chicks, were assessed by carrageenan-induced oedema and Randall-Sellito pressure models, respectively. By the Agar diffusion method, bacterial growth inhibition by a 15% w/w CFHE ointment was investigated on Salmonella typhi, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus. Aureus, and Streptococcus pyogenes. RESULTS: All concentrations of CFHE ointment significantly reduced (p < 0.0001) wound area by 29-41% posttreatment. CFHE (1.6-100 mg/ml) promoted platelet aggregation (p ≤ 0.0001) by 37-67% (IC50: 3.1-6.2 mg/ml). There were improved wound tissue reepithelization, fibroblast proliferation, angiogenesis, and collagen deposition with 15% CFHE ointment treatment. CFHE ointment significantly (p ≤ 0.0001) and dose-dependently reduced thigh oedema and showed a significant (p ≤ 0.05) analgesic effect. In vitro, 15% CFHE ointment caused >100% growth inhibition of selected bacteria. CONCLUSION: The hydroethanolic leaf extract of Cnestis ferruginea possesses wound healing, platelet aggregation, anti-inflammatory, analgesic, and antimicrobial properties and, hence, could be effective in the management of open and some closed wounds.