Glucuronidation of carcinogenic arylamines and their N-hydroxy derivatives by rat and human phenol UDP-glucuronosyltransferases of the UGT1 gene complex

Abstract

Since carcinogenic arylamines are sequentially oxidized and conjugated with glucuronic acid, differences in glucuronidation may critically determine the toxic potential of these compounds. Therefore, N-glucuronidation of 1- and 2-naphthylamine (1-NA and 2-NA),4-aminobiphenyl(4-ABP) and their N-hydroxy derivatives was investigated using rat and human liver microsomes and V79 cell-expressed phenol UDP-glucuronosyltransferases (UGT) of the UGT1 gene complex. Cell-expressed UGTs included rat and human UGT1.6, which are known to conjugate planar phenols, and human UGT1.7, conjugating both planar and bulky phenol. (i) N-Glucuronidation of 1- and 2-NA and of N-hydroxy-2-NA was inducible by 3-methylcholanthrene in rat liver microsomes whereas N-glucuronidation of the bulky arylamines 4-ABP and N-hydroxy-4-ABP was not. In support of these findings mutagenicity of N-hydroxy-2-NA in the Ames test was markedly reduced upon addition of UDP-glucuronic acid using liver homogenates from 3-methylcholanthrene-treated rats. (ii) With cell-expressed rat UGT1.6, non-carcinogenic 1-NA was conjugated with the highest rate and 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 derivative, whereas UGT1.7 showed broader substrate specificity, including 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-hyroxy derivatives.

Pharmacogenomics of human UDP-glucuronosyltransferase enzymes

“…A detailed analysis of data available in the literature revealed that overall, the UGT1A1 isoform seems to be expressed at a lower level in approximately 0-3% of the Asian population, 2-13% of the Caucasian population and up to 16-19% of Africans (Table 2). On the other hand, the UGT1A1*33 (TA 5 ) and UGT1A1*34 (TA 8 ) polymorphisms found initially in the African-American population are also observed at much lower frequencies in Caucasians. 67,118 Although interindividual variations in UGT1A1 expression are thought to be largely because of the UGT1A1*28 polymorphism, at least one additional common polymorphic variant has been reported in the literature.…”

“…66,126 Two genetic epidemiological studies were designed to investigate the association between genetic variability in the UGT1A1 promoter region and the risk of breast cancer: one involving African-American subjects and the other, Caucasian women. 66,67 Based on functional studies, 66 UGT1A1 promoter alleles were divided into two classes; low transcriptional activity alleles (A(TA) 7 TAA or A(TA) 8 TAA) and high transcriptional activity alleles (A(TA) 5 TAA or A(TA) 6 TAA). It was postulated that breast cancer cases have a higher frequency of low transcriptional activity alleles (high-risk genotypes) compared to controls.…”

“…Indeed, virtually all classes of drugs are substrates for UGTs and this pathway has been estimated to account for approximately 35% of all drugs metabolized by phase II drugmetabolizing enzymes (DMEs). 1 At least two additional biological functions are attributed to UGTs: (i) the contribution of UGTs is determinant in the mechanism of protection against some toxic dietary components, tobacco smoke carcinogens and various environmental pollutants [2][3][4][5][6][7][8][9] and (ii) they represent key elements in the homeostasis of a number of endogenous molecules, including bilirubin, steroid and thyroid hormones, fatty acids as well as biliary acids. [10][11][12][13][14] In recent years, breakthroughs in the pharmacogenomic field support the concept that genetic factors related to genes encoding DMEs, transporters and drug targets play a significant role in the clinical response to therapeutic drugs.…”

“…The Pharmacogenomics Journal UGT1A6 Common UGT1A6 Polymorphisms UGT1A6 is a phenol-metabolizing UGT, primarily involved in the glucuronidation of simple phenols and planar arylamines 5,93 that mediates the conjugation of many currently prescribed drugs including antidepressants, neuroleptics and b-adrenoreceptor blockers. 93,[129][130][131][132][133][134] The UGT1A6 gene has been found to be polymorphic with at least four alleles characterized by three SNPs in the coding sequence.…”

4‐Aminobiphenyl induces liver DNA adducts in both neonatal and adult mice but induces liver mutations only in neonatal mice

“…It has been suggested that 4-ABP induces lower DNA adduct levels and tumor incidence in the livers of males relative to females due to the higher chemical conjugation capability of males. [54][55][56][57][58] The similarity of DNA adduct levels induced by 4-ABP in male and female neonatal mice implies a similar level of arylamine metabolism in these mice.…”