The glucuronidation of hydroxylated metabolites of benzo[a]pyrene and 2-acetylaminofluorene by cDNA-expressed human UDP-glucuronosyltransferases.
The capacity of four cDNA-expressed human liver UDP-glucuronosyltransferases (UGT), UGT1*6, UGT2B7, UGT2B10 and UGT2B11, to glucuronidate hydroxylated metabolites of benzo[a]pyrene (B[a]P) and 2-acetylaminofluorene (AAF) has been investigated. UGT1*6 and UGT2B7 glucuronidated a range of B[a]P and AAF metabolites with a degree of regiospecificity, although UGTs 2B10 and 2B11 were inactive towards all compounds screened. UGT2B7 glucuronidated the B[a]P trans 4,5- and 7,8-dihydrodiols and the 1-,2-,4-,5-,6-,8-,9- and 10-monophenols. In contrast, UGT1*6 lacked activity towards the dihydrodiols and metabolized a more limited range of monophenols, namely 4-,5-,8- and 12-hydroxyB[a]P. Both UGT2B7 and UGT1*6 glucuronidated N, 1-,3- and 8-hydroxyAAF, but 5-hydroxyAAF was metabolised only by UGT1*6. Neither enzyme glucuronidated 3-,7- and 11-hydroxyB[a]P and 7- and 9-hydroxyAAF, although these compounds were all metabolised by human liver microsomal UGTs. The results suggest that the relative content of UGT isoforms in a cell or tissue will be important for determining the extent to which a particular carcinogen/mutagen is deactivated.
Jin
C J
CJ
Department of Clinical Pharmacology, Flinders Medical Centre, Bedford Park, Australia.
Miners
J O
JO
Burchell
B
B
Mackenzie
P I
PI
D015073:2-Acetylaminofluorene / Q000378:metabolism*; D001564:Benzo(a)pyrene / Q000378:metabolism*; D002460:Cell Line; D018076:DNA, Complementary; D005965:Glucuronates / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism
D018076:DNA, Complementary; D005965:Glucuronates; D001564:Benzo(a)pyrene; D015073:2-Acetylaminofluorene; D014453:Glucuronosyltransferase