Glucuronidation of arachidonic and linoleic acid metabolites by human UDP-glucuronosyltransferases

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. 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. Linoleic acid (LA), an 18-carbon fatty acid, is an abundant polyunsaturated fatty acid (PUFA) in phospholipids, the major component of the lipid bilayer of cell membranes (1Gottard S. Relevance of fatty acid and eicosanoids to clinical and preventive medicine.Prog. Lipid Res. 1986; 25: 1-4Google Scholar). Arachidonic acid (AA), a 20-carbon fatty acid, is also present in substantial amounts in cellular membranes and is produced from LA by chain elongation and desaturation (1Gottard S. Relevance of fatty acid and eicosanoids to clinical and preventive medicine.Prog. Lipid Res. 1986; 25: 1-4Google Scholar, 2Chaudry A.A. Wahle K.W. McClinton S. Moffat L.E. Arachidonic acid metabolism in benign and malignant prostatic tissue in vitro: effects of fatty acids and cyclooxygenase inhibitors.Int. J. Cancer. 1994; 57: 176-180Google Scholar). 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)(3Nie D. Che M. Grignon D. Tang K. Honn K.V. Role of eicosanoids in prostate cancer progression.Cancer Metastasis Rev. 2001; 20: 195-206Google Scholar). The hydroxylated metabolites of LA and AA are important mediators of many physiological and pathophysiological processes (3Nie D. Che M. Grignon D. Tang K. Honn K.V. Role of eicosanoids in prostate cancer progression.Cancer Metastasis Rev. 2001; 20: 195-206Google Scholar). For instance, prostaglandins, the products of cyclooxygenases, regulate vascular homeostasis, kidney function, ovulation, and parturition (4Vane J.R. Bakhle Y.S. Botting R.M. Cyclooxygenases 1 and 2.Annu. Rev. Pharmacol. Toxicol. 1998; 38: 97-120Google Scholar). Although the physiological functions of HETE, the hydroxylated metabolites of AA, are not fully characterized, accumulating evidence indicates that they are involved in a wide spectrum of biological activities, such as platelet activation and aggregation, immune system activity, cell differentiation, and apoptosis (5Paubert-Braquet M. Mencia Huerta J.M. Cousse H. Braquet P. Effect of the lipidic lipidosterolic extract of Serenoa repens (Permixon) on the ionophore A23187-stimulated production of leukotriene B4 (LTB4) from human polymorphonuclear neutrophils.Prostaglandins Leukot. Essent. Fatty Acids. 1997; 57: 299-304Google Scholar, 6Funk C.D. The molecular biology of mammalian lipoxygenases and the quest for eicosanoid functions using lipoxygenase-deficient mice.Biochim. Biophys. Acta. 1996; 1304: 65-84Google Scholar, 7Payan D.G. Goetzl E.J. Specific suppression of human T lymphocyte function by leukotriene B4.J. Immunol. 1983; 131: 551-553Google Scholar). The products of cyclooxygenases and lipoxygenases have also been implicated in several forms of epithelial cell cancers, especially in prostate cancer, for which recent results indicate that they are important angiogenic and mitogenic factors (3Nie D. Che M. Grignon D. Tang K. Honn K.V. Role of eicosanoids in prostate cancer progression.Cancer Metastasis Rev. 2001; 20: 195-206Google Scholar, 8Nie D. Hillman G.G. Geddes T. Tang K. Grignon K.V. Platelet-type 12-lipoxygenase in human prostate carcinoma stimulate angiogenesis and tumor growth.Cancer Res. 1998; 58: 4047-4051Google Scholar, 9Nie D. Tang K. Diglio C. Honn K.V. Eicosanoid regulation of angiogenesis: role of endothelial arachidonate 12-lipoxygenase.Blood. 2000; 95: 2304-2311Google Scholar, 10Kelavkar U.P. Nixon J.B. Cohen C. Dillehay D. Eling T.E. Badr K.F. Overexpression of 15-lipoxygenase-1 in PC-3 human prostate cancer cells increases tumorigenesis.Carcinogenesis. 2001; 22: 1765-1773Google Scholar, 11Ghosh J. Myers C.E. Inhibition of arachinodate 5-lipoxygenase triggers massive apoptosis in human prostate cancer cells.Proc. Natl. Acad. Sci. USA. 1998; 95: 13182-13187Google Scholar). Although the catabolism of these PUFAs involves several P450 enzymes, the significant contribution of glucuronidation in their clearance has been recently established (12Wheelan P. Hankin J.A. Bahri B. Guenette D. Murphy R. Metabolic transformation of leukotriene B4 in primary cultures of hepatocytes.J. Pharmacol. Exp. Ther. 1999; 288: 326-334Google Scholar, 13Jude A.R. Little J.M. Freeman J.P. Evans J.E. Radominska-Pandya A. Grant D.F. Linoleic acid diols are novel substrates for human UDP-glucuronosyltransferases.Arch. Biochem. Biophys. 2000; 380: 294-302Google Scholar, 14Jude A.R. Little J.M. Czernik P.J. Tephly T.R. Grant D.F. Radominska-Pandya A. Glucuronidation of linoleic acid diols by human microsomal and recombinant UDP-glucuronosyltransferases: identification of UGT2B7 as the major isoform involved.Arch. Biochem. Biophys. 2001; 389: 176-186Google Scholar, 15Jude A.R. Little J.M. Bull A.W. Podgorski I. Radominska-Pandya A. 13-Hydroxy- and 13-oxooctadecadienoic acids: novel substrates for human UDP-glucuronosyltransferases.Drug Metab. Dispos. 2001; 29: 652-655Google Scholar, 16Ford-Hutchinson A.W. Leukotriene B4 in inflammation.Crit. Rev. Immunol. 1990; 10: 1-12Google Scholar). Indeed, several authors have reported the presence in the urine of glucuronidated PUFAs (17Duran M. Ketting D. van Vossen R. Beckering T.E. Dorland L. Bruinvis L. Wadman S.K. Octanoylglucuronide excretion in patients with a defective oxidation of medium-chain fatty acids.Clin. Chim. Acta. 1985; 152: 253-260Google Scholar, 18Costa C.C.G. Dorland L. Kroon M. Taveres de Almeida I. Jakobs C. Duran M. 3-, 6- And 7-hydroxyoctanoic acids are metabolites of medium-chain triglycerides and excretion in urine as glucuronides.J. Mass Spectrom. 1996; 31: 633-638Google Scholar, 19Sacerdoti D. Balazy M. Angeli P. Gatta A. McGiff J.C. Eicosanoid excretion in hepatic cirrhosis.J. Clin. Invest. 1997; 100: 1264-1270Google Scholar, 20Kuhara T. Matsumoto I. Ohno M. Ohura T. Identification and quantification of octanoyl glucuronide in the urine of children who ingested medium-chain triglycerides.Biomed. Environ. Mass Spectrom. 1986; 13: 595-598Google Scholar). 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 (21Dutton G.J. Glucuronidation of Drugs and Other Compounds. CRC Press, Boca Raton, FL1980Google Scholar). Conjugation by UGT enzymes is also an important pathway of elimination for several endogenous compounds, namely steroids, thyroid hormones, retinoic acids, and bilirubin. Based on amino acid sequence homology, UGT enzymes have been classified into two families, UGT1 and UGT2 (22Mackenzie P.I. Owens I.S. Burchell B. Bock K.W. Bairoch A. A. S. M. T. D. P. J. J.R. H. Tephly T.R. K.F. The on 1997; Scholar). In the UGT1 family is by a of on I.S. the human UGT1 in and Res. Scholar). These to which are to to the of that functional T. C. S. S. Owens I.S. are the human UGT1 2001; Scholar). The UGT1 members are to the conjugation of and A. Czernik P.J. Little J.M. P.I. and functional of UDP-glucuronosyltransferases.Drug Metab. Rev. 1999; 31: Scholar, A. M. C. M. C. A. D. S. of UDP-glucuronosyltransferases on Biochem. 1999; Scholar). The UGT2 family is into two which is expressed in and UGT2B of the human UDP-glucuronosyltransferases and regulation in the 2001; Scholar). The the UGT2B members have been on and of is of D. A. and of the human a of UGT2B and on 2000; Scholar). In members of the UGT2B family have been UGT2B4 M. A. and of a UDP-glucuronosyltransferase by a 1999; Scholar, D. S. Burchell B. of a human liver microsomal UDP-glucuronosyltransferase J. UGT2B7 P.I. and of two members of the human liver UDP-glucuronosyltransferase Biophys. Res. Scholar, Owens I.S. and of human liver UDP-glucuronosyltransferase in and as primary 1990; UGT2B10 M. A. and of a human orphan Biophys. Res. 1998; P.I. and of two members of the human liver UDP-glucuronosyltransferase Biophys. Res. D. A. and of the human a of UGT2B and on 2000; M. A. and of a novel a human UDP-glucuronosyltransferase on 1996; and recently D. M. A. and of the a novel human 2001; Scholar). All UGT2B have been stably in the HK293 cell and was demonstrated that these enzymes and their have conjugation acids, acids, and hormones, namely and D. M. A. and of the a novel human 2001; Scholar, D. A. activity, and tissue of human UGT2B subfamily 2001; Scholar). UGT2B10 and not activity for substrates tested M. A. and of a human orphan Biophys. Res. 1998; Scholar). The of was to the role of UGT enzymes in the conjugation of the AA and LA All human UGT1A and UGT2B enzymes stably in the HK293 cell of endogenous activity, have been data that several UGT enzymes conjugate AA metabolites 12-HETE, 15-HETE, and leukotriene B4 (LTB4), and the LA 13-HODE. and were from 12-HETE, 15-HETE, and were from and was from was from and was by HK293 cells were from the and human liver microsomes were from the HK293 cells were in containing of of and a containing and cell were by R. Tephly C.D. Tephly T.R. The glucuronidation of and by human and Metab. Dispos. 1998; Scholar). and cell were as M. A. and of a UDP-glucuronosyltransferase by a 1999; Scholar). UGT1A1, UGT1A3, UGT1A4, and were by from kidney and liver as reported C. M. A. The and human expressed in tissues, are 1999; Scholar). were by HK293 cells stably UGT1A1, UGT1A3, UGT1A4, UGT1A8, UGT2B7, UGT2B11, or were in 1 and and the were for to and were and were for to the microsomal which were in and were using 1 to of the and to of from in and in a of were by of and by for 1 as M. A. and of a novel a human UDP-glucuronosyltransferase on 1996; Scholar). The screening for the of the UGT with fatty acid substrates was using 1 for that demonstrated with UGT were in the presence of 1 for 1 with all UGT enzymes, for which was for in to reaction The microsomal from HK293 which not endogenous UGT enzymes, was as a for the glucuronidation The products from the glucuronidation of the were by using an system was with a using a 1 in and 1 in from to was and to of the system the of The was to a mass with an in the The mass was in mass in was of the of and UGT2B7 for LTB4 was by 1 to of the in the presence of 1 1 as reported M. A. and of a novel a human UDP-glucuronosyltransferase on 1996; whereas of and for the UGT2B7 were of to of the from HK293 cells stably UGT2B7 were in the presence of LTB4 and of from to which to the of UGT2B7 for C.D. Tephly T.R. The glucuronidation of and by human and Metab. Dispos. 1998; Scholar). were for 1 and glucuronidation products were by the for of human liver microsomal with LA and AA metabolites and the system of quantification by were with LTB4 and for which the of conjugated products by human liver microsomes has been demonstrated (12Wheelan P. Hankin J.A. Bahri B. Guenette D. Murphy R. Metabolic transformation of leukotriene B4 in primary cultures of hepatocytes.J. Pharmacol. Exp. Ther. 1999; 288: 326-334Google Scholar). in LTB4 was in the the of the was whereas two major metabolites to the derivatives of LTB4 of and (Fig. data indicate that the molecules were into the LTB4 and a glucuronic acid not and that the of or of LTB4 was not be The was also conjugated by hepatic UGT enzymes in was observed of also to a (Fig. Glucuronidation reaction by human liver microsomes of and 15-HETE, and was also assessed as in derivatives were by for of the substrates for and which were conjugated into two the two fatty acids the to a and the of was not of liver microsomes with 12-HETE, 15-HETE, and for in the transformation of of the whereas and LTB4 were converted by and which UGT enzymes are for the glucuronidation of the substrates were with all recombinant UGT1 and UGT2 family members Glucuronidation of LTB4 was observed with UGT1A1, UGT1A3, UGT1A8, and for glucuronidation activity demonstrated that UGT1A9 is the isoform that conjugation of the UGT1A family members, UGT1A9 demonstrated wide the HETEs and 13-HODE. UGT1A1, UGT1A3, and also showed 12-HETE, 15-HETE, and 13-HODE. LA and AA metabolites also appear to be good substrates for the UGT2B subfamily members, especially for UGT2B4 and UGT2B7, which conjugate all HETEs and 13-HODE. and which are to conjugate 12-HETE, and UGT2B10 and UGT2B11, which are considered orphan enzymes since no conjugation activity has so far been demonstrated with these enzymes, conjugated 12-HETE, 15-HETE, and whereas UGT2B10 also glucuronidated the of the from of UGT2B10 with 12-HETE, a to a of was that the of conjugation activity fatty acid derivatives observed with UGT be to UGT was in the presence of Glucuronidation of glucuronidation was observed with all enzymes, with the of UGT2B11, and the no far not of the of metabolites to glucuronide derivatives by microsomal from human liver and cells stably human UGT hydroxyeicosatetraenoic leukotriene which UGT was microsomal were with 1 UDP-glucuronic acid, of for were by and the were to The were by spectrometry. indicates that glucuronidation activity was whereas indicates that no conjugation was in a HETE, hydroxyeicosatetraenoic leukotriene which UGT was microsomal were with 1 UDP-glucuronic acid, of for were by and the were to The were by spectrometry. indicates that glucuronidation activity was whereas indicates that no conjugation was the of glucuronidation fatty acid all that with were in analyses with microsomal of human liver and recombinant UGT enzymes demonstrated of LTB4 The glucuronidation were and for UGT1A3, UGT1A8, and UGT2B7 (Fig. Although screening analyses demonstrated that LTB4 the of conjugation not quantification the for of UGT for LTB4 was using microsomal of stably and in were and for and UGT2B7, and the glucuronidation to the was and for and UGT2B7, of LTB4 conjugation by recombinant human UGT from HK293 cells stably or UGT2B7 were in the presence of 1 to LTB4 and 1 for the of in that UGT2B7 the and the the of to the glucuronidation of UGT enzymes 12-HETE, and observed with UGT2B7 is an of these with glucuronidation of and (Fig. of the UGT2B7 for and and to glucuronidation of 1 and the and PUFAs for glucuronidation by UGT2B7 of the major were in the presence of Interestingly, glucuronidation of LTB4 of was whereas a of LTB4 was observed (Fig. to was observed the of which to the of UGT2B7 for C.D. Tephly T.R. The glucuronidation of and by human and Metab. Dispos. 1998; Scholar). The enzymes a family of enzymes that PUFAs such as LA and AA into a variety of products (3Nie D. Che M. Grignon D. Tang K. Honn K.V. Role of eicosanoids in prostate cancer progression.Cancer Metastasis Rev. 2001; 20: 195-206Google Scholar). These enzymes are expressed in and several tissues, such as the mammalian tissues, and and recent data indicate that their products are implicated in several forms of epithelial cell (3Nie D. Che M. Grignon D. Tang K. Honn K.V. Role of eicosanoids in prostate cancer progression.Cancer Metastasis Rev. 2001; 20: 195-206Google Scholar, 8Nie D. Hillman G.G. Geddes T. Tang K. Grignon K.V. Platelet-type 12-lipoxygenase in human prostate carcinoma stimulate angiogenesis and tumor growth.Cancer Res. 1998; 58: 4047-4051Google Scholar, 9Nie D. Tang K. Diglio C. Honn K.V. Eicosanoid regulation of angiogenesis: role of endothelial arachidonate 12-lipoxygenase.Blood. 2000; 95: 2304-2311Google Scholar, 10Kelavkar U.P. Nixon J.B. Cohen C. Dillehay D. Eling T.E. Badr K.F. Overexpression of 15-lipoxygenase-1 in PC-3 human prostate cancer cells increases tumorigenesis.Carcinogenesis. 2001; 22: 1765-1773Google Scholar, 11Ghosh J. Myers C.E. Inhibition of arachinodate 5-lipoxygenase triggers massive apoptosis in human prostate cancer cells.Proc. Natl. Acad. Sci. USA. 1998; 95: 13182-13187Google Scholar, J.A. J.A. and of and their to Biochem. Biophys. 1998; Scholar, S. acid is the mitogenic for linoleic in in Res. 1999; Scholar, S. K. S. S. of leukotriene B4 from Leukot. Essent. Fatty Acids. Scholar). is that the inactivation of metabolites in several tissues, the oxidation processes as a by a that is also to be present in the to further their elimination from the (17Duran M. Ketting D. van Vossen R. Beckering T.E. Dorland L. Bruinvis L. Wadman S.K. Octanoylglucuronide excretion in patients with a defective oxidation of medium-chain fatty acids.Clin. Chim. Acta. 1985; 152: 253-260Google Scholar, 18Costa C.C.G. Dorland L. Kroon M. Taveres de Almeida I. Jakobs C. Duran M. 3-, 6- And 7-hydroxyoctanoic acids are metabolites of medium-chain triglycerides and excretion in urine as glucuronides.J. Mass Spectrom. 1996; 31: 633-638Google Scholar, 19Sacerdoti D. Balazy M. Angeli P. Gatta A. McGiff J.C. Eicosanoid excretion in hepatic cirrhosis.J. Clin. Invest. 1997; 100: 1264-1270Google Scholar, 20Kuhara T. Matsumoto I. Ohno M. Ohura T. Identification and quantification of octanoyl glucuronide in the urine of children who ingested medium-chain triglycerides.Biomed. Environ. Mass Spectrom. 1986; 13: 595-598Google Scholar). Conjugation by UGT expressed in the liver as a pathway is considered important for the elimination of of the human UDP-glucuronosyltransferases and regulation in the 2001; Scholar). evidence also for endogenous substances such as steroids, thyroid hormones, and retinoic acids, UGT enzymes are in to the in several the and prostate A. M. C. M. C. A. D. S. of UDP-glucuronosyltransferases on Biochem. 1999; Scholar). In the present glucuronidation of 12-HETE, 15-HETE, and was investigated. The data showed that several UGT enzymes are capable of converting LA and AA metabolites into glucuronide of UGT enzymes metabolites that the glucuronidation activity be important in the pathway of Interestingly, several of the UGT enzymes capable of are expressed in the liver A. M. C. M. C. A. D. S. of UDP-glucuronosyltransferases on Biochem. 1999; Scholar, D. A. activity, and tissue of human UGT2B subfamily 2001; Scholar). Glucuronidation of LA and AA metabolites was using human liver a tissue most UGT enzymes, UGT1A8, and All substrates tested were efficiently conjugated by liver microsomes to polar derivatives containing the glucuronyl as assessed by analyses demonstrated of liver UGT1A and UGT2B since the to the conjugation of of and 15-HETE, as as of 13-HODE. the screening analyses with stably expressed UGT enzymes in HK293 the wide of UGT enzymes for metabolites with Indeed, UGT enzymes with and 20-carbon substrates carrying two and the of is also observed for the of the since 12-HETE, 15-HETE, and were conjugated by the of Although is a in conjugation of fatty acid metabolites by UGT enzymes, screening analyses for For instance, which with M. A. and of a novel a human UDP-glucuronosyltransferase on 1996; conjugated whereas the conjugated 13-HODE. observed for hormones, these results that the be conjugated by several UGT enzymes, whereas has a of substrates A. M. C. M. C. A. D. S. of UDP-glucuronosyltransferases on Biochem. 1999; Scholar, D. A. activity, and tissue of human UGT2B subfamily 2001; Scholar). The most results were with UGT2B10 and UGT2B11, which conjugate and all HETE These enzymes were the on that is conjugated by all UGT enzymes, no has so far been M. A. and of a human orphan Biophys. Res. 1998; Scholar). for the that two UGT enzymes, UGT2B10 and UGT2B11, the glucuronidation of LA and AA in several UGT enzymes that were considered for also be implicated in the glucuronidation of these screening analyses the significant activity of UGT enzymes the of their conjugation a role of UGT enzymes in their Indeed, of LTB4 glucuronidation by UGT2B7 with that of substrates showed glucuronidation For instance, the glucuronidation for LTB4 by the observed for the endogenous of UGT2B7 with the glucuronidation observed to D. A. activity, and tissue of human UGT2B subfamily 2001; Scholar). Interestingly, UGT2B7 glucuronidation for LTB4 are to of which is as a for glucuronidation D. A. activity, and tissue of human UGT2B subfamily 2001; Scholar). analyses demonstrated that UGT2B7 has a for LTB4 for D. A. activity, and tissue of human UGT2B subfamily 2001; Scholar, C.D. Tephly T.R. The glucuronidation of and by human and Metab. Dispos. 1998; the LTB4 glucuronidation as expressed by the was which was in the of the glucuronidation observed for with also demonstrated glucuronidation for LTB4 and the on the glucuronidation of UGT enzymes that showed the activity for and screening analyses were to the of observed with glucuronidation were that for hormones, especially for and 15-HETE, which have of and of the UGT2B7 for the tested substrates was glucuronidation were to observed with The of glucuronidation observed in the present are also in with data reported by of LA conjugation by UGT2B7 A.R. Little J.M. Czernik P.J. Tephly T.R. Grant D.F. Radominska-Pandya A. Glucuronidation of linoleic acid diols by human microsomal and recombinant UDP-glucuronosyltransferases: identification of UGT2B7 as the major isoform involved.Arch. Biochem. Biophys. 2001; 389: 176-186Google Scholar). In the human and cell whereas and regulate angiogenesis and prostate cell differentiation, (3Nie D. Che M. Grignon D. Tang K. Honn K.V. Role of eicosanoids in prostate cancer progression.Cancer Metastasis Rev. 2001; 20: 195-206Google Scholar, 10Kelavkar U.P. Nixon J.B. Cohen C. Dillehay D. Eling T.E. Badr K.F. Overexpression of 15-lipoxygenase-1 in PC-3 human prostate cancer cells increases tumorigenesis.Carcinogenesis. 2001; 22: 1765-1773Google Scholar, 11Ghosh J. Myers C.E. Inhibition of arachinodate 5-lipoxygenase triggers massive apoptosis in human prostate cancer cells.Proc. Natl. Acad. Sci. USA. 1998; 95: 13182-13187Google Scholar). that UGT2B11, and are expressed in the prostate D. A. activity, and tissue of human UGT2B subfamily 2001; Scholar, H. M. A. of enzymes in the human prostate by in and Clin. Metab. 2000; the present data that prostate tissue has the to conjugate the In of these UGT enzymes, namely and also and metabolites in the prostate A. M. C. M. C. A. D. S. of UDP-glucuronosyltransferases on Biochem. 1999; Scholar). for also a role in prostate and and stimulate the of prostate cancer UGT enzymes expressed in the prostate be implicated in the metabolism of two of endogenous data further the that several the to and products A. M. C. M. C. A. D. S. of UDP-glucuronosyltransferases on Biochem. 1999; Scholar, of in cells by Exp. Scholar, A. M. D. C. A. L. S. J. human and by Biochem. Scholar). In since was demonstrated that the of UGT enzymes in cells be by several such as and is to that of PUFAs metabolites in such as human prostate also be by in activity C. A. of and by in the human prostatic cancer cell 1996; Scholar, M. C. A. Effect of factors on UDP-glucuronosyltransferase and activity in the cell Biochem. 1998; Scholar). The of UGT enzymes on two of products is further by analyses that demonstrated that and PUFAs in for the or two In was also to an of LTB4 conjugation by UGT2B7 of activation of glucuronidation activity of substrates was recently reported for conjugation by J.A. K. of UDP-glucuronosyltransferase by the of substrates and to human liver Metab. Dispos. whereas was not observed for the glucuronidation of by Although the be an of the in system further be to conjugation in The of UGT enzymes capable of in such as the liver and also a role of these enzymes in the catabolism of and produced leukotrienes, and a of UGT enzymes in such as and regulation of their Although especially are to efficiently the and inactivation of the role of the liver also be of major since tissue is also for the elimination of LA and AA metabolites into Murphy of leukotriene B4 in of in leukotriene B4 1990; Scholar, H. M. microsomal metabolism of leukotriene B4 in of and and Scholar, M. and of leukotriene B4 in J. 1990; Scholar). In summary, our data that several UGT enzymes are capable of LA and AA activity is expressed in several the is to that UGT enzymes to of important endogenous substances and/or to from The authors to for This was by the of and a from the de

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