Department of Clinical Pharmacology, School of Medicine, Faculty of Health Sciences, Flinders University, Adelaide, South Australia, Australia.
Br J Clin Pharmacol. 2013 Oct;76(4):587-602. doi: 10.1111/bcp.12086.
Although knowledge of human renal cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes and their role in xenobiotic and endobiotic metabolism is limited compared with hepatic drug and chemical metabolism, accumulating evidence indicates that human kidney has significant metabolic capacity. Of the drug metabolizing P450s in families 1 to 3, there is definitive evidence for only CYP 2B6 and 3A5 expression in human kidney. CYP 1A1, 1A2, 1B1, 2A6, 2C19, 2D6 and 2E1 are not expressed in human kidney, while data for CYP 2C8, 2C9 and 3A4 expression are equivocal. It is further known that several P450 enzymes involved in the metabolism of arachidonic acid and eicosanoids are expressed in human kidney, CYP 4A11, 4F2, 4F8, 4F11 and 4F12. With the current limited evidence of drug substrates for human renal P450s drug-endobiotic interactions arising from inhibition of renal P450s, particularly effects on arachidonic acid metabolism, appear unlikely. With respect to the UGTs, 1A5, 1A6, 1A7, 1A9, 2B4, 2B7 and 2B17 are expressed in human kidney, whereas UGT 1A1, 1A3, 1A4, 1A8, 1A10, 2B10, 2B11 and 2B15 are not. The most abundantly expressed renal UGTs are 1A9 and 2B7, which play a significant role in the glucuronidation of drugs, arachidonic acid, prostaglandins, leukotrienes and P450 derived arachidonic acid metabolites. Modulation by drug substrates (e.g. NSAIDs) of the intrarenal activity of UGT1A9 and UGT2B7 has the potential to perturb the metabolism of renal mediators including aldosterone, prostaglandins and 20-hydroxyeicosatetraenoic acid, thus disrupting renal homeostasis.
虽然与肝药物和化学代谢相比，人们对人类肾脏细胞色素 P450（CYP）和 UDP-葡糖醛酸基转移酶（UGT）酶及其在外源性和内源性代谢物中的作用的了解有限，但越来越多的证据表明，人类肾脏具有显著的代谢能力。在家族 1 至 3 的药物代谢 CYP 中，只有 CYP2B6 和 3A5 在人类肾脏中表达有明确的证据。CYP1A1、1A2、1B1、2A6、2C19、2D6 和 2E1 不在人类肾脏中表达，而 CYP2C8、2C9 和 3A4 表达的数据则存在争议。此外，还已知几种参与花生四烯酸和类二十烷酸代谢的 P450 酶在人类肾脏中表达，包括 CYP4A11、4F2、4F8、4F11 和 4F12。根据目前关于人类肾脏 P450 药物底物的有限证据，由于抑制肾脏 P450 而产生的药物-内源性相互作用，特别是对花生四烯酸代谢的影响，似乎不太可能发生。至于 UGTs，1A5、1A6、1A7、1A9、2B4、2B7 和 2B17 在人类肾脏中表达，而 UGT1A1、1A3、1A4、1A8、1A10、2B10、2B11 和 2B15 则不表达。表达最丰富的肾脏 UGTs 是 1A9 和 2B7，它们在药物、花生四烯酸、前列腺素、白三烯和 P450 衍生的花生四烯酸代谢物的葡萄糖醛酸化中发挥重要作用。药物底物（如 NSAIDs）对 UGT1A9 和 UGT2B7 的肾内活性的调节有可能扰乱包括醛固酮、前列腺素和 20-羟二十碳四烯酸在内的肾介质的代谢，从而破坏肾内稳态。
