GLUCURONIDATION OF CARCINOGENIC ARYLAMINES AND THEIR N-HYDROXY DERIVATIVES BY RAT AND HUMAN PHENOL UDP-GLUCURONOSYLTRANSFERASES OF THE UGT1GENE-COMPLEX
A. Orzechowski et al., GLUCURONIDATION OF CARCINOGENIC ARYLAMINES AND THEIR N-HYDROXY DERIVATIVES BY RAT AND HUMAN PHENOL UDP-GLUCURONOSYLTRANSFERASES OF THE UGT1GENE-COMPLEX, Carcinogenesis, 15(8), 1994, pp. 1549-1553
Since carcinogenic arylamines are sequentially oxidized and conjugated
with glucuronic acid, differences in glucuronidation may critically d
etermine the toxic potential of these compounds. Therefore, N-glucuron
idation of 1- and 2-naphthylamine (1-NA and 2-NA), 4-aminobiphenyl (4-
ABP) and their N-hydroxy derivatives was investigated using rat and hu
man liver microsomes and V79 cell-expressed phenol UDP-glucuronosyltra
nsferases (UGT) of the UGT1 gene complex. Cell-expressed UGTs included
rat and human UGT1.6, which are known to conjugate planar phenols, an
d human UGT1.7, conjugating both planar and bulky phenols. (i) N-Glucu
ronidation of 1- and 2-NA and of Nhydroxy-2-NA was inducible by 3-meth
ylcholanthrene in rat liver microsomes whereas N-glucuronidation of th
e bulky arylamines CABP and N-hydroxy-4-ABP was not. In support of the
se findings mutagenicity of N-hydroxy-2-NA in the Ames test was marked
ly reduced upon addition of UDP-glucuronic acid using liver homogenate
s from 3-methylcholanthrene-treated rats. (ii) With cell-expressed rat
UGT1.6, non-carcinogenic 1-NA was conjugated with the highest rate an
d with higher affinity than 2-NA. UGT1.6 showed poor activity towards
N-hydroxy-4-ABP and 4-ABP. (iii) Substrate specificity of human UGT1.6
also appeared to be limited to planar 1-NA, 2-NA and its N-hydroxy de
rivative, whereas UGT1.7 showed broader substrate specificity, includi
ng the bulky arylamine 4-ABP and its N-hydroxy derivative. The results
suggest marked differences in substrate specificity of different UGT
isozymes for arylamines and their N-hydroxy derivatives.