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Methylmercury (MeHg) and 2,3,7,8-tetrachlorodibenzodioxin (TCDD) are potent environmental pollutants implicated in the modulation of xenobiotic-metabolizing enzymes, particularly the cytochrome P450 1 family (CYP1) which is regulated by the aryl hydrocarbon receptor (AHR). However, the co-exposure to MeHg and TCDD raises concerns about their potential combined effects, necessitating thorough investigation. The primary objective of this study was to investigate the individual and combined effects of MeHg and TCDD on AHR-regulated CYP1 enzymes in mouse extrahepatic tissues. Therefore, C57BL/6 mice were administrated with MeHg (2.5 mg/kg) in the absence and presence of TCDD (15 μg/kg) for 6 and 24 h. The AHR-regulated CYP1 mRNA and protein expression levels were measured in the heart, lung, and kidney, using RT real-time PCR and western blot, respectively. Interestingly, treatment with MeHg exhibited mainly inhibitory effect, particularly, it decreased the basal level of Cyp1a1 and Cyp1a2 mRNA and protein, and that was more evident at the 24 h time point in kidney followed by heart. Similarly, when mice were co-exposed, MeHg was able to reduce the TCDD-induced Cyp1a1 and Cyp1a2 expression, however, MeHg potentiated kidney Cyp1b1 mRNA expression, opposing the observed change on its protein level. Also, MeHg induced antioxidant NAD(P)H:quinone oxidoreductase (NQO1) mRNA and protein in kidney, while heme-oxygenase (HO-1) mRNA was up-regulated in heart and kidney. In conclusion, this study reveals intricate interplay between MeHg and TCDD on AHR-regulated CYP1 enzymes, with interesting inhibitory effects observed that might be significant for procarcinogen metabolism. Varied responses across tissues highlight the potential implications for environmental health., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Hydroxyeicosatetraenoic acids (HETEs) are hydroxylated arachidonic acid (AA) metabolites that are classified into midchain, subterminal, and terminal HETEs. Hydroxylation results in the formation of R and S enantiomers for each HETE, except for 20-HETE. HETEs have multiple physiological and pathological effects. Several studies have demonstrated sex-specific differences in AA metabolism in different organs. In this study, microsomes from the heart, liver, kidney, lung, intestine, and brain of adult male and female Sprague-Dawley rats were isolated and incubated with AA. Thereafter, the enantiomers of all HETEs were analyzed by liquid chromatography-tandem mass spectrometry. We found significant sex- and enantiospecific differences in the formation levels of different HETEs in all organs. The majority of HETEs, especially midchain HETEs and 20-HETE, showed significantly higher formation rates in male organs. In the liver, the R enantiomer of several HETEs showed a higher formation rate than the corresponding S enantiomer (e.g., 8-, 9-, and 16-HETE). On the other hand, the brain and small intestine demonstrated a higher abundance of the S enantiomer. 19(S)-HETE was more abundant than 19(R)-HETE in all organs except the kidney. Elucidating sex-specific differences in HETE levels provides interesting insights into their physiological and pathophysiological roles and their possible implications for different diseases., Competing Interests: The authors declare there are no competing interests.

Purpose: Evaluating the role of cystone, a polyherbal preparation, in protecting cancer patients against cisplatin-induced nephrotoxicity, and its impact on the cytotoxic activity of cisplatin., Methods: A prospective open-label randomized controlled trial conducted on 49 cancer patients who received six cycles of 70 mg/m(2) cisplatin-based regimens. The study comprised two groups, a control group (A) in which 28 patients received cisplatin without cystone supplement, and an experimental group (B) in which 21 patients received cisplatin with cystone supplement. Renal function parameters including serum creatinine, creatinine clearance, blood urea, and serum cystatin C were compared between both groups throughout chemotherapy cycles. Patient response to treatment was evaluated in both groups after 3rd and 6th cycles., Results: At the end of the study, mean levels of serum creatinine, blood urea, and serum cystatin C were significantly lower, whereas creatinine clearance was significantly higher in group (B) compared with group (A). In group (B), there was no significant difference between mean levels of renal markers at baseline and after completion of treatment; while significant changes were observed in group (A). Grading of acute kidney injury according to Common Terminology Criteria for Adverse Events revealed significantly better renal status among patients in group (B) "grades 0 and 1 in 76 and 24 % of the patients, respectively" compared with group (A) "grades 0, 1, and 2 in 36, 32, and 32 % of the patients, respectively". Based on Response Evaluation Criteria in Solid Tumors, there was no significant difference between both groups., Conclusions: Cystone can protect cancer patients from cisplatin nephrotoxicity without interfering with its antitumor activity.