Nakamura M, Imaoka S, Miura K, Tanaka E, Misawa S, Funae Y
Institute of Community Medicine, University of Tsukuba, Ibaraki, Japan.
Biochem Pharmacol. 1994 Nov 1;48(9):1743-6. doi: 10.1016/0006-2952(94)90460-x.
To examine the effects of cyclosporin A (CsA) on renal cytochrome P450 forms, CsA was administered to rats, and the renal levels of P450 were determined by immunoblotting. CsA treatment for 17 days increased total renal P450 content by 40% with a concomitant elevation of the omega- and (omega-1)-hydroxylation activities of lauric acid. Arachidonic acid omega-hydroxylation activity was also induced 2-fold by treatment with CsA for 17 days. Among the P450 forms, CYP4A2 was induced significantly, whereas CYP2C23, CYP4A1 and CYP4A8 were unaffected. These changes were accompanied by slight but significant increases in blood urea nitrogen and systolic blood pressure. These data suggest that CsA increased arachidonic acid omega-hydroxylation activity by the induction of CYP4A2. The specific induction of CYP4A2 may be related to CsA-induced nephrotoxicity and elevated blood pressure, because omega-hydroxyarachidonic acid is a potent vasoconstrictor.
为研究环孢素A（CsA）对肾细胞色素P450亚型的影响，将CsA给予大鼠，并通过免疫印迹法测定肾脏P450水平。连续17天给予CsA治疗可使肾脏总P450含量增加40%，同时月桂酸的ω-和（ω-1）-羟化活性升高。连续17天给予CsA治疗也可使花生四烯酸ω-羟化活性诱导增加2倍。在P450亚型中，CYP4A2被显著诱导，而CYP2C23、CYP4A1和CYP4A8未受影响。这些变化伴随着血尿素氮和收缩压轻微但显著的升高。这些数据表明，CsA通过诱导CYP4A2增加了花生四烯酸ω-羟化活性。CYP4A2的特异性诱导可能与CsA诱导的肾毒性和血压升高有关，因为ω-羟基花生四烯酸是一种有效的血管收缩剂。
