Hepatic Transcript Profiles of Cytochrome P450 Genes Predict Sex Differences in Drug Metabolism

Abstract

Safety assessments of new drug candidates are an important part of the drug development and approval process. Often, possible sex-associated susceptibilities are not adequately addressed, and better assessment tools are needed. We hypothesized that hepatic transcript profiles of cytochrome P450 (Cyp) enzymes can be used to predict sex-associated differences in drug metabolism, and possible adverse events. Comprehensive hepatic transcript profiles were generated for F344 rats of both sexes at nine ages, from 2 weeks (pre-weaning) to 104 weeks (elderly). Large differences in the transcript profiles of 29 drug metabolizing enzymes and transporters (DMETs)were found between adult males and females (8-52 weeks). Using the PharmaPendium database, 41 drugs were found to be metabolized by one or two Cyp enzymes encoded by sexually dimorphic mRNAs, and thus were candidates for evaluation of possible sexually dimorphic metabolism and/or toxicities. Suspension cultures of primary hepatocytes from three male and three female adult rats (10-13 weeks old) were used to evaluate the metabolism of 11 drugs predicted to have sexually dimorphic metabolism. The pharmacokinetics of the drug or its metabolite was analyzed by liquid chromatography/tandem mass spectrometry using multiple reaction monitoring. Of those drugs with adequate metabolism, the predicted significant sex-different metabolism was found for six of seven drugs, with half-lives 37%-400% longer in female hepatocytes than in male hepatocytes. Thus, in this rat model, transcript profiles may allow identification of potential sex-related differences in drug metabolism.

Promoter Hypomethylation and miR-145-5p Downregulation- Mediated HDAC11 Overexpression Promotes Sorafenib Resistance and Metastasis of Hepatocellular Carcinoma Cells

“…By GSEA, the potential action mechanisms of HDAC11 in modulation of sorafenib resistance in HCC were explored. The result suggested that drug metabolism cytochrome P450 pathway was significantly enriched in HDAC11-low expression group, indicating that HDAC11 might promote HCC cell sorafenib resistance by inactivation of drug metabolism cytochrome P450 pathway, which has been confirmed to be involved in drug metabolism in liver (Almazroo et al, 2017;Fuscoe et al, 2020). Moreover, survival analysis also demonstrated that HDAC11 was a promising prognostic biomarker in HCC with vascular invasion.…”

Sex-, Age-, and Race/Ethnicity-Dependent Variations in Drug-Processing and NRF2-Regulated Genes in Human Livers

“…Female rats have higher expression of Mrp3 (Fuscoe et al, 2020). In the liver of Oatp1a4-null mice, females had higher expression of Mrp4, Mdr1a, Mdr1b, and Abcg5 (Zhang et al, 2013).…”

Beyond the X Factor: Relevance of Sex Hormones in NAFLD Pathophysiology

“…Sex dimorphic expression of hepatic enzymes active in the metabolism of drugs, steroids, and environmental chemicals, especially cytochromes P450 (CYPs) and sulfotransferases [ 45 , 46 , 47 ], might account for the well-known sex differences in detoxification and drug metabolism and, therefore, for the differences in pharmacokinetics and pharmacodynamics between the two sexes [ 42 ].…”