Regulation of ABC transporters by sex steroids may explain differences in drug resistance between sexes

Abstract

Drug efficacy is dependent on the pharmacokinetics and pharmacodynamics of therapeutic agents. Tight junctions, detoxification enzymes, and drug transporters, due to their localization on epithelial barriers, modulate the absorption, distribution, and the elimination of a drug. The epithelial barriers which control the pharmacokinetic processes are sex steroid hormone targets, and in this way, sex hormones may also control the drug transport across these barriers. Thus, sex steroids contribute to sex differences in drug resistance and have a relevant impact on the sex-related efficacy of many therapeutic drugs. As a consequence, for the further development and optimization of therapeutic strategies, the sex of the individuals must be taken into consideration. Here, we gather and discuss the evidence about the regulation of ATP-binding cassette transporters by sex steroids, and we also describe the signaling pathways by which sex steroids modulate ATP-binding cassette transporters expression, with a focus in the most important ATP-binding cassette transporters involved in multidrug resistance.

Prostate Cancer and the Mevalonate Pathway

“…Correspondingly, the inhibition of fatty acid synthase (FASN) enhances the immune response to castration-resistant PCa cell line tumors and decreases the expression and transcriptional activity of AR and the AR-variant splicing 7, resulting in a better response to hormone treatment [85]. The secretion of cholesterol into the intracellular space is regulated by ATP-binding cassette (ABC) transporters, and data have shown the tissuedependent regulation of ABC transporters by estrogens, progesterone, and androgens [86].…”