Characterization of benzo(a)pyrene-trans-7,8-dihydrodiol glucuronidation by human tissue microsomes and overexpressed UDP-glucuronosyltransferase enzymes.
作者： Frederick A Beland , Chantal Guillemette , Doris Wiener , Philip Lazarus , M Matilde Marques
DOI:
关键词:
摘要: UDP-glucuronosyltransferase (UGT)-mediated glucuronidation of benzo(a)pyrene-trans-7,8-dihydrodiol (BPD), precursor to the potent mutagen benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide, may be an important pathway in detoxification benzo(a)pyrene. To better characterize this humans, high-pressure liquid chromatography (HPLC) was used detect glucuronide conjugates BPD formed vitro. Three peaks were detected by HPLC after incubation racemic with human liver microsomes; these identified as monoglucuronides chromatography-mass spectrometry analysis. Proton nuclear magnetic resonance spectroscopy isolated fractions, combined analysis products from microsomal incubations purified benzo(a)pyrene-trans-7S,8S-dihydrodiol [(+)-BPD] and benzo(a)pyrene-trans-7R,8R-dihydrodiol [(-)-BPD] forms BPD, indicated that peak 1 contained 7-glucuronide 7S,8S-BPD (BPD-7S-Gluc), 2 a mixture 7R,8R-BPD (BPD-7R-Gluc) 8-glucuronide (BPD-8S-Gluc), 3 7R, 8R-BPD (BPD-8R-Gluc). In microsomes, (BPD-7S-Gluc) largest observed, whereas microsomes aerodigestive tract tissues, (both BPD-7R-Gluc BPD-8S-Gluc) observed. The enzymes UGT1A1 UGT2B7 BPD-7S-Gluc major diastereomer, UGT1A8 UGT1A10, extrahepatic present tract, preferentially both BPD-8S-Gluc. addition, UGT1A9 UGT1A7 BPD-7R-Gluc. No detectable glucuronidating activity against observed UGT1A3, UGT1A4, UGT1A6, UGT2B4, UGT2B15, or UGT2B17. affinity individual UGT determined K(m) UGT1A10 > for (-)-BPD approximately (+)-BPD. These results suggest several UGTs play role overall UGT1A1, UGT1A7, UGT1A9, potentially playing procarcinogenic enantiomer, stereospecific exhibited different is consistent tissue-specific patterns diastereomer formation expression.
aacrjournals.org参考文章(48)
Balder Bob, Robert Van Helden, Verberg Govert, Polynuclear aromatic compounds ,(1962)
Ida S. Owens, Joseph K. Ritter, Gene structure at the human UGT1 locus creates diversity in isozyme structure, substrate specificity, and regulation. Progress in Nucleic Acid Research and Molecular Biology. ,vol. 51, pp. 305- 338 ,(1995) , 10.1016/S0079-6603(08)60882-X
Peter I. Mackenzie, Louise Rodbourn, Takashi Iyanagi, Glucuronidation of Carcinogen Metabolites by Complementary DNA-expressed Uridine 5′-Diphosphate Glucuronosyltransferases Cancer Research. ,vol. 53, pp. 1529- 1533 ,(1993)
E M Oturu, T R Tephly, M D Green, Stable expression of a human liver UDP-glucuronosyltransferase (UGT2B15) with activity toward steroid and xenobiotic substrates. Drug Metabolism and Disposition. ,vol. 22, pp. 799- 805 ,(1994)
B L Coffman, T R Tephly, C D King, M D Green, Cloning and stable expression of a cDNA encoding a rat liver UDP-glucuronosyltransferase (UDP-glucuronosyltransferase 1.1) that catalyzes the glucuronidation of opioids and bilirubin. Molecular Pharmacology. ,vol. 47, pp. 1101- 1105 ,(1995)
Jong Y. Park, Philip Lazarus, Andrew J. Dannenberg, Thomas R. Tephly, Sharon E. Murphy, Qing Ren, Glucuronidation of the lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) by rat UDP-glucuronosyltransferase 2B1. Drug Metabolism and Disposition. ,vol. 27, pp. 1010- 1016 ,(1999)
Birgit L. Coffman, Gladys R. Rios, Thomas R. Tephly, Christopher D. King, The glucuronidation of opioids, other xenobiotics, and androgens by human UGT2B7Y(268) and UGT2B7H(268). Drug Metabolism and Disposition. ,vol. 26, pp. 73- 77 ,(1998)
Peter I. Mackenzie, Gladys R. Rios, Thomas R. Tephly, Christopher D. King, Mitchell D. Green, Comparison of Stably Expressed Rat UGT1.1 and UGT2B1 in the Glucuronidation of Opioid Compounds Drug Metabolism and Disposition. ,vol. 25, pp. 251- 255 ,(1997)
H V Gelboin, Benzo[alpha]pyrene metabolism, activation and carcinogenesis: role and regulation of mixed-function oxidases and related enzymes. Physiological Reviews. ,vol. 60, pp. 1107- 1166 ,(1980) , 10.1152/PHYSREV.1980.60.4.1107
B Burchell, T Ebner, Substrate specificities of two stably expressed human liver UDP-glucuronosyltransferases of the UGT1 gene family. Drug Metabolism and Disposition. ,vol. 21, pp. 50- 55 ,(1993)