Sex-specific UGT expression and function: prevalence, potential mechanisms and significance

Sex and gender influence pharmacotherapy outcomes, including adverse drug effects which are nearly twice as common in women. Sex differences in drug responses involve factors as diverse as body composition, physiology, and prescribing patterns. Many drugs show higher exposure in women, which can be partly attributed to sex-differences in processes that control drug disposition such as metabolism and transport.

This article reviews sex differences in the expression and function of the critical phase II drug-metabolizing enzymes, UDP-glucuronosyltransferases (UGTs). We curate the literature on sex-biased UGT expression in human tissues, describe the evidence for UGT-mediated sex-differences in drug exposure, and critically evaluate whether UGTs contribute to different drug outcomes in males and females. Relevant literature was identified by searching PubMed with terms including UDP-glucuronosyltransferase/UGT, glucuronidation/glucuronide, sex, gender, male, female, men, and women.

Several examples of sex-biased UGT expression and drug glucuronidation were identified; however, evidence of clinical impact was more limited. Significant data gaps limit our understanding of the prevalence and importance of sex-biased glucuronidation. Novel methodologies for tissue-level metabolite sampling together with increased sex-aware analysis of clinical/preclinical data, could help address gaps and reveal new avenues for enhancing pharmacotherapy outcomes for all genders.