Abstract
Arachidonic acids (AA) and linoleic acids (LAs) are metabolized, in several tissues, to hydroxylated metabolites that are important mediators of many physiological and pathophysiological processes. The conjugation of leukotriene B4 (LTB4), 5-hydroxyeicosatetraenoic acid (HETE), 12-HETE, 15-HETE, and 13-hydroxyoctadecadienoic acid (HODE) by the human UDP-glucuronosyltransferase (UGT) enzymes was investigated. All substrates tested were efficiently conjugated by human liver microsomes to polar derivatives containing the glucuronyl moiety as assessed by mass spectrometry. The screening analyses with stably expressed UGT enzymes in HK293 showed that glucuronidation of LTB4 was observed with UGT1A1, UGT1A3, UGT1A8, and UGT2B7, whereas UGT1A1, UGT1A3, UGT1A4, and UGT1A9 also conjugated most of the HETEs and 13-HODE. LA and AA metabolites also appear to be good substrates for the UGT2B subfamily members, especially for UGT2B4 and UGT2B7 that conjugate all HETE and 13-HODE. Interestingly, UGT2B10 and UGT2B11, which are considered as orphan enzymes since no conjugation activity has so far been demonstrated with these enzymes, conjugated 12-HETE, 15-HETE, and 13-HODE. In summary, our data showed that several members of UGT1A and UGT2B families are capable of converting LA and AA metabolites into glucuronide derivatives, which is considered an irreversible step to inactivation and elimination of endogenous substances from the body.
Highlights
Arachidonic acids (AA) and linoleic acids (LAs) are metabolized, in several tissues, to hydroxylated metabolites that are important mediators of many physiological and pathophysiological processes
Arachidonic acid (AA), a 20-carbon fatty acid, is present in substantial amounts in cellular membranes and is produced from LA by chain elongation and desaturation [1, 2]. These two PUFAs are further converted into a) prostaglandins or thromboxanes by cyclooxygenases and/or b) hydroxyeicosatetraenoic acids (HETEs), leukotrienes, or 13-hydroxyoctadecadieneoic acid (13-hydroxyoctadecadienoic acid (HODE)) by lipoxygenases (Fig. 1) [3]
Glucuronidation of arachidonic and LA metabolites by human liver microsomes To ascertain the experimental conditions used for incubation of human liver microsomal preparations with LA and AA metabolites and the system of quantification by liquid chromatography-mass spectrometry (LC-MS), incubations were first conducted with leukotriene B4 (LTB4) and its 20-COOH metabolite, for which the formation of conjugated products by human liver microsomes has already been demonstrated [12]
Summary
Arachidonic acids (AA) and linoleic acids (LAs) are metabolized, in several tissues, to hydroxylated metabolites that are important mediators of many physiological and pathophysiological processes. Arachidonic acid (AA), a 20-carbon fatty acid, is present in substantial amounts in cellular membranes and is produced from LA by chain elongation and desaturation [1, 2] These two PUFAs are further converted into a) prostaglandins or thromboxanes by cyclooxygenases and/or b) hydroxyeicosatetraenoic acids (HETEs), leukotrienes, or 13-hydroxyoctadecadieneoic acid (13-HODE) by lipoxygenases (Fig. 1) [3]. Several authors have reported the presence in the urine of glucuronidated PUFAs [17,18,19,20] This conjugation reaction is catalyzed by UDP-glucuronosyltransferases (UGTs), a family of endoplasmic reticulum membrane-bound enzymes that transfer the glucuronic moiety from the UDP-glucuronic acid (UDPGA) to a wide variety of small lipophilic molecules carrying a functional group containing oxygen, nitrogen, or sulfur [21]. UGT2B10 and UGT2B11 did not demonstrate conjugating activity for over 100 substrates tested [33]
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