Renal drug metabolism in humans: the potential for drug-endobiotic interactions involving cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT)
Renal drug metabolism in humans: the potential for drug-endobiotic interactions involving cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT)
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DOI：
10.1111/bcp.12086
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发表时间：
2013-10-01
影响因子：
3.4
通讯作者：
Miners, John O.
中科院分区：
文献类型：
--
作者：
Knights, Kathleen M.;Rowland, Andrew;Miners, John O.
尽管与肝脏药物和化学代谢相比，人类肾脏细胞色素P450 （CYP）和udp -葡萄糖醛基转移酶（UGT）酶及其在外源性和内源性代谢中的作用的知识有限，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 ~ 3的药物代谢p450中，有明确证据表明只有CYP 2B6和3A5在人类肾脏中表达。CYP 1A1、1A2、1B1、2A6、2C19、2D6和2E1在人肾中不表达，而CYP 2C8、2C9和3A4的表达数据不明确。进一步了解，参与花生四烯酸和类二十烷酸代谢的几种P450酶CYP 4A11、4F2、4F8、4F11和4F12在人肾中表达。由于目前关于人体肾脏p450的药物底物的证据有限，抑制肾脏p450引起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。UGT中，1A5、1A6、1A7、1A9、2B4、2B7和2B17在人肾中表达，而UGT 1A1、1A3、1A4、1A8、1A10、2B10、2B11和2B15不表达。肾ugt中表达最丰富的是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产物的糖醛酸化中发挥重要作用。药物底物（如非甾体抗炎药）对UGT1A9和UGT2B7肾内活性的调节有可能扰乱肾介质的代谢，包括醛固酮、前列腺素和20-羟基二碳四烯酸，从而破坏肾脏稳态。
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.