O-Glucuronidation of the lung carcinogen 4-(methylnitrosamino)-1- (3-pyridyl)-1-butanol (NNAL) by human UDP-glucuronosyltransferases 2B7 and 1A9.
4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone and its major metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), are potent lung carcinogens in animals. UGT-mediated O-glucuronidation of NNAL is an important detoxification pathway for these carcinogens. To better characterize this pathway in humans, we screened a series of UGT-overexpressing cell lines and baculosome preparations for their ability to O-glucuronidate NNAL and examined multiple human liver and lung specimens for NNAL-glucuronidating activity and their levels of expression of NNAL-glucuronidating UGTs. Human liver microsomal fractions exhibited significant levels of NNAL-glucuronidating activity, with the NNAL-Gluc II diastereomer formed at a rate 3.4 times that observed for NNAL-Gluc I. As with liver microsomal fractions, NNAL-Gluc II was the major diastereomer formed by homogenates from UGT2B7-overexpressing HK293 cells or UGT2B7-overexpressing baculosomes; the major diastereomer formed by homogenates from UGT1A9-overexpressing V79 cells was NNAL-Gluc I. No significant O-glucuronidating activity of NNAL was detected in UGT1A1-, UGT1A4-, UGT1A6-, UGT2B4-, or UGT2B15-overexpressing HK293 or V79 cell homogenates, or in UGT1A1-, UGT1A3-, UGT1A7-, or UGT1A10-overexpressing baculosomes. Significant levels of UGT2B7 mRNA were detected by reverse transcriptase-polymerase chain reaction in human liver and at low levels in human lung specimens. UGT1A9 mRNA was detected in liver but not in lung. These results suggest that although both UGT2B7 and UGT1A9 play an important role in the overall glucuronidation of NNAL in humans, UGT2B7 potentially plays an important role in the detoxification of NNAL in the lung.
Ren
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Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
Murphy
S E
SE
Zheng
Z
Z
Lazarus
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P
D000818:Animals; D002273:Carcinogens / Q000493:pharmacokinetics*; D002460:Cell Line; D006224:Cricetinae; D020719:Glucuronides / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000139:chemically induced*; D009602:Nitrosamines / Q000493:pharmacokinetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D002273:Carcinogens; D020719:Glucuronides; D007527:Isoenzymes; D009602:Nitrosamines; D012333:RNA, Messenger; C051577:4-(methylnitrosoamino)-4-(3-pyridyl)-1-butanol; D014453:Glucuronosyltransferase