Glucuronidation of carcinogen metabolites by complementary DNA-expressed uridine 5'-diphosphate glucuronosyltransferases.
Five UDP glucuronosyltransferases (UGT) were synthesized from complementary DNAs expressed in COS 7 cells and were tested for their capacities to glucuronidate a range of 2-acetylaminofluorene and benzo(a)pyrene-hydroxylated metabolites. Three forms, UGT1*06, UGT2B1, and UGT2B2 [names of UGT forms follow recommended nomenclature (B. B. Burchell et al., DNA Cell Biol., 10: 487-494, 1991)], had similar capacities to glucuronidate the reactive metabolite, N-hydroxy-2-acetylaminofluorene. The less reactive 1-, 3-, 5-, and 8-hydroxy derivatives of this aromatic amine were glucuronidated by UGT1*06 and UGT2B2 to varying degrees, but these were not substrates of UGT2B1. The three isozymes also glucuronidated phenolic metabolites of benzo(a)pyrene. UGT1*06 was more active toward 2- and 5-hydroxybenzo(a)pyrene, whereas UGT2B1 preferentially glucuronidated the 4- and 11-hydroxy derivatives and UGT2B2 preferentially glucuronidated the 1-, 2-, 8-, and 9-hydroxy metabolites. Two other UDP glucuronosyltransferases, UGT2B3 and UGT2B6, that glucuronidated testosterone when expressed in COS 7 cells were both inactive toward all the carcinogen metabolites tested. These results demonstrate that the glucuronidation of metabolites of 2-acetylaminofluorene and benzo(a)pyrene is mediated by at least three UDP glucuronosyltransferases and that each form glucuronidates a unique spectrum of metabolites.
Mackenzie
P I
PI
Department of Clinical Pharmacology, Flinders University School of Medicine, Bedford Park South Australia.
Rodbourn
L
L
Iyanagi
T
T
D015073:2-Acetylaminofluorene / Q000031:analogs & derivatives / Q000378:metabolism*; D000818:Animals; D001564:Benzo(a)pyrene / Q000031:analogs & derivatives / Q000378:metabolism*; D002478:Cells, Cultured; D014453:Glucuronosyltransferase / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D013379:Substrate Specificity
D001564:Benzo(a)pyrene; D015073:2-Acetylaminofluorene; D014453:Glucuronosyltransferase