Kavalactone metabolism in rat liver microsomes.
The specific CYP enzymes involved in kavalactone (KLT) metabolism and their kinetics have not been fully examined. This study used rat liver microsomes (RLM) to determine kavain (KA), methysticin (MTS) and desmethoxyyangonin (DMY) enzyme kinetic parameters, to elucidate the major CYP450 isoforms involved in KLT metabolism and to examine gender differences in KLT metabolism. Formation of the major KLT metabolites was first-order, consistent with classic enzyme kinetics. In both male and female RLM, clotrimazole (CLO) was the most potent inhibitor of KA and MTS metabolism. This suggests CYP3A1/3A23 (females) and CYP3A2 (males) are the main isoenzymes involved in the metabolism of these KLTs in rats, while the roles of CYP1A2, -2 C6, -2 C9, -2E1 and -3A4 are limited. Desmethoxyyangonin metabolism was equally inhibited by cimetidine (CIM) and CLO in females, and CIM and nortriptyline in males. This implies that DMY metabolism involves CYP2C6 and CYP2C11 in males, and CPY2C12 in females. CYP3A1/3A23 may also be involved in females.
Faculty of Pharmacy, University of Sydney, NSW 2006, Australia.
Shuang
S
Fu
Anthony
A
Rowe
Iqbal
I
Ramzan
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D005260:Female; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D011714:Pyrans / Q000378:metabolism; D011753:Pyrones / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors
C107882:7,8-dihydromethysticin; D007527:Isoenzymes; D008565:Membrane Proteins; D011714:Pyrans; D011753:Pyrones; C502657:desmethoxyyangonin; D001189:Aryl Hydrocarbon Hydroxylases; C465260:Cyp3a2 protein, rat; C465138:Cyp3a23-3a1 protein, rat; D051544:Cytochrome P-450 CYP3A; C076881:methysticin; C011889:kavain