13-Hydroxy- and 13-oxooctadecadienoic acids: Novel substrates for human UDP-glucuronosyltransferases

Although there are numerous studies of glucuronidation of endogenous compou nds, information on the glucuronidation of fatty acids is lacking. In the p resent studies, both linoleic acid (LA) and its biologically active oxidize d derivatives, 13-hydroxyoctadecadienoic acid (13-HODE) and 13-oxooctadecad ienoic acid (13-OXO), have been shown to be effective substrates for human liver UDP-glucuronosyltransferases (UGT) and recombinant UGT2B7. LA (carbox yl glucuronide) and 13-OXO (carboxyl glucuronide, unproven) were actively g lucuronidated by human liver microsomes (HLM) and human recombinant UGT2B7 with similar activities, in the range of 2 nmol/mg . min. The hydroxyl deri vative of LA, 13-HODE, was glucuronidated at both the hydroxyl and carboxyl functions with carboxyl glucuronidation predominating (ratio of COOH/OH, 2 :1). For all substrates, the K-m for formation of the carboxyl-linked glucu ronide was in the range of 100 to 200 muM while that for the hydroxyl-linke d glucuronide was somewhat lower (> 100 muM). This is the first demonstrati on of glucuronidation of LA and its oxidized derivatives, 13-HODE and 13-OX O, by HLM and recombinant UGT2B7.