Laboratory of Clinical Pharmaceutics and Therapeutics, College of Pharmaceutical Sciences, Ritsumeikan University.
Graduate School of Biomedical and Health Sciences, Hiroshima University.
Biol Pharm Bull. 2021;44(11):1617-1634. doi: 10.1248/bpb.b21-00332.
The CYP3A subfamily, which includes isoforms CYP3A4, CYP3A5, and CYP3A7 in humans, plays important roles in the metabolism of various endogenous and exogenous substances. Gene and protein expression of CYP3A4, CYP3A5, and CYP3A7 show large inter-individual differences, which are caused by many endogenous and exogenous factors. Inter-individual differences can cause negative outcomes, such as adverse drug events and disease development. Therefore, it is important to understand the variations in CYP3A expression caused by endo- and exogenous factors, as well as the variation in the metabolism and kinetics of endo- and exogenous substrates. In this review, we summarize the factors regulating CYP3A expression, such as bile acids, hormones, microRNA, inflammatory cytokines, drugs, environmental chemicals, and dietary factors. In addition, variations in CYP3A expression under pathological conditions, such as coronavirus disease 2019 and liver diseases, are described as examples of the physiological effects of endogenous factors. We also summarize endogenous and exogenous substrates metabolized by CYP3A isoforms, such as cholesterol, bile acids, hormones, arachidonic acid, vitamin D, and drugs. The relationship between the changes in the kinetics of these substrates and the toxicological effects in our bodies are discussed. The usefulness of these substrates and metabolites as endogenous biomarkers for CYP3A activity is also discussed. Notably, we focused on discrimination between CYP3A4, CYP3A5, and CYP3A7 to understand inter-individual differences in CYP3A expression and function.
CYP3A 亚家族，包括人类中的 CYP3A4、CYP3A5 和 CYP3A7 同工酶，在各种内源性和外源性物质的代谢中发挥重要作用。CYP3A4、CYP3A5 和 CYP3A7 的基因和蛋白表达存在很大的个体间差异，这是由许多内源性和外源性因素引起的。个体间差异可导致不良药物事件和疾病发展等负面后果。因此，了解内源性和外源性因素引起的 CYP3A 表达变化以及内源性和外源性底物的代谢和动力学变化非常重要。在这篇综述中，我们总结了调节 CYP3A 表达的因素，如胆汁酸、激素、microRNA、炎症细胞因子、药物、环境化学物质和饮食因素。此外，还描述了内源性因素（如 2019 年冠状病毒病和肝脏疾病）引起的 CYP3A 表达变化的病理生理效应。我们还总结了 CYP3A 同工酶代谢的内源性和外源性底物，如胆固醇、胆汁酸、激素、花生四烯酸、维生素 D 和药物。讨论了这些底物动力学的变化与我们体内毒理学效应之间的关系。还讨论了这些底物和代谢物作为 CYP3A 活性的内源性生物标志物的有用性。值得注意的是，我们重点关注 CYP3A4、CYP3A5 和 CYP3A7 的区分，以了解 CYP3A 表达和功能的个体间差异。
