Induction of cytochrome P450 isozymes in rat renal microsomes by cyclosporin A.
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.
Institute of Community Medicine, University of Tsukuba, Ibaraki, Japan.
M
M
Nakamura
S
S
Imaoka
K
K
Miura
E
E
Tanaka
S
S
Misawa
Y
Y
Funae
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology* / Q000633:toxicity; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D015151:Immunoblotting; D007527:Isoenzymes / Q000096:biosynthesis*; D007668:Kidney / Q000187:drug effects / Q000201:enzymology*; D007850:Lauric Acids / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley
C000717351:Cyp2c23 protein, rat; D007527:Isoenzymes; D007850:Lauric Acids; C030358:lauric acid; D016718:Arachidonic Acid; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; D000090762:Cytochrome P-450 CYP2J2