Importance of UDP-glucuronosyltransferase 1A10 (UGT1A10) in the detoxification of polycyclic aromatic hydrocarbons: decreased glucuronidative activity of the UGT1A10139Lys isoform.
UDP-glucuronosyltransferase 1A10 (UGT1A10) is an extrahepatic enzyme expressed in aerodigestive tract tissues that exhibits significant glucuronidation activity against the important procarcinogenic benzo(a)pyrene (BaP) metabolite, BaP-trans-7,8-dihydrodiol (BPD), and the UGT1A10 codon 139 (Glu>Lys) polymorphism was previously implicated in risk for orolaryngeal cancer by Elahi et al. in their 2003 study. To better assess the potential role of UGT1A10 in risk for tobacco-related cancers, the glucuronidation activity of UGT1A10 was compared with that of other known UGT enzymes against selected polycyclic aromatic hydrocarbons, and the effects of the codon 139 polymorphism on UGT1A10 function were examined in vitro. UGT1A10 exhibited considerably more glucuronidation activity as determined by Vmax/Km against 3-hydroxy (OH)-BaP, 7-OH-BaP, 9-OH-BaP, and 1-OH-pyrene than any other UGT1A family member. Although a kinetic comparison using Vmax could not be performed against family 2B UGTs, UGT1A10 exhibited a 1.7- to 254-fold lower Km than active family 2B UGTs against 3-OH-BaP, 7-OH-BaP, and 1-OH-pyrene. A significantly (p < 0.01) higher Vmax/Km was observed for homogenates from wild-type UGT1A10139Glu-overexpressing cells against all four BaP metabolites tested (3-OH-BaP, 7-OH-BaP, 9-OH-BaP, and BPD). A similarly significant (p < 0.05) increase in Vmax/Km was observed for homogenates from wild-type UGT1A10139Glu-overexpressing cells against 1-OH-pyrene. Significant differences in Km were observed for homogenates from wild-type UGT1A10139Glu-overexpressing cells against 1-OH-pyrene (p < 0.05) and 3-OH-BaP (p < 0.01). Reverse transcription-polymerase chain reaction of total lung RNA showed low levels of UGT1A10 expression in human lung tissue. Together, these studies implicate UGT1A10 as an important detoxifier of polycyclic aromatic hydrocarbons in humans and that the UGT1A10 codon 139 polymorphism may be an important determinant in risk for tobacco-related cancers.
Dellinger
Ryan W
RW
Cancer Prevention and Control Program, Division of Population Sciences and Cancer Prevention, Penn State Cancer Institute, Penn State University College of Medicine, PA 17033, USA.
Fang
Jia-Long
JL
Chen
Gang
G
Weinberg
Rebecca
R
Lazarus
Philip
P
D001580:Benzopyrenes / Q000378:metabolism; D002273:Carcinogens / Q000378:metabolism; D045744:Cell Line, Tumor; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008658:Inactivation, Metabolic; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D008168:Lung / Q000201:enzymology; D016297:Mutagenesis, Site-Directed; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D014162:Transfection
D001580:Benzopyrenes; D002273:Carcinogens; D020719:Glucuronides; D007527:Isoenzymes; D012333:RNA, Messenger; C476725:bilirubin uridine-diphosphoglucuronosyl transferase 1A10; D014453:Glucuronosyltransferase