Glucuronidation: An Important Mechanism for Detoxification of Benzo[<i>a</i>]Pyrene Metabolites in Aerodigestive Tract Tissues

Zheng, Zhong; Fang, Jia‐Long; Lazarus, Philip

doi:10.1124/dmd.30.4.397

Cited by 133 publications

(122 citation statements)

References 28 publications

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“…UGTs are also expressed in a wide variety of tissues, including brain, prostate, uterus, breast, placenta and kidney, to name only a few. 11,[76][77][78][79][80] The molecular genetics of human UGTs is now more clearly understood, with evidence for the existence of distinct subfamilies, which comprise more than 26 genes or cDNAs (Figure 2). Eighteen of them correspond to functional proteins and are encoded by two gene families, UGT1 and UGT2 that are, based on their sequence similarities, further divided into three subfamilies: UGT1A, UGT2A and UGT2B (for detailed information see Mackenzie et al 81 ).…”

Section: A Brief Overview Of the Glucuronidation Pathway And Human Ugtsmentioning

confidence: 99%

Pharmacogenomics of human UDP-glucuronosyltransferase enzymes

2003

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UDP-glucuronosyltransferase (UGT) enzymes comprise a superfamily of key proteins that catalyze the glucuronidation reaction on a wide range of structurally diverse endogenous and exogenous chemicals. Glucuronidation is one of the major phase II drug-metabolizing reactions that contributes to drug biotransformation. This biochemical process is also involved in the protection against environmental toxicants, carcinogens, dietary toxins and participates in the homeostasis of numerous endogenous molecules, including bilirubin, steroid hormones and biliary acids. Over the years, significant progress was made in the field of glucuronidation, especially with regard to the identification of human UGTs, study of their tissue distribution and substrate specificities. More recently, the degree of allelic diversity has also been revealed for several human UGT genes. Some polymorphic UGTs have demonstrated a significant pharmacological impact in addition to being relevant to drug-induced adverse reactions and cancer susceptibility. This review focuses on human UGTs, the description of the nature of polymorphic variations and their functional impact. The pharmacogenomic implication of polymorphic UGTs is presented, more specifically the role of UGT polymorphisms in modifying cancer risk and their impact on individual risk to drug-induced toxicities.

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Section: A Brief Overview Of the Glucuronidation Pathway And Human Ugtsmentioning

confidence: 99%

Pharmacogenomics of human UDP-glucuronosyltransferase enzymes

2003

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“…Because UGT1A10 seemed to be the most active human enzyme in dopamine glucuronidation, we evaluated the tissue specificity of expression of this isoform. Although studies with some tissues were done previously, there were inconsistencies in results, particularly regarding whether this enzyme is expressed in liver (Strassburg et al, 1997(Strassburg et al, , 1998(Strassburg et al, , 1999Mojarrabi and Mackenzie, 1998;Cheng et al, 1999;Zheng et al, 2002;Li et al, 2007;Nakamura et al, 2008). In addition, because dopamine is an important neurotransmitter in the brain, we wanted to find out whether UGT1A10 is expressed in the brain.…”

Section: Itä Aho Et Almentioning

confidence: 99%

“…UGT1A10 was considered an extrahepatic UGT that is mainly expressed in the intestine (Strassburg et al, 1997(Strassburg et al, , 1998(Strassburg et al, , 1999Mojarrabi and Mackenzie, 1998;Cheng et al, 1999;Zheng et al, 2002). However, in a recent study, low expression levels of UGT1A10 were detected in liver and hepatocytes (Li et al, 2007;Nakamura et al, 2008).…”

mentioning

confidence: 99%

Dopamine Is a Low-Affinity and High-Specificity Substrate for the Human UDP-Glucuronosyltransferase 1A10

Itäaho¹,

Court²,

Uutela³

et al. 2008

Drug Metab Dispos

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ABSTRACT:The purpose of this work was to identify human UDP-glucuronosyltransferases (UGTs) capable of glucuronidating dopamine. Using a sensitive liquid chromatography-tandem mass spectrometry method, we screened all 19 known human UGTs and found that only one enzyme, UGT1A10, catalyzed dopamine glucuronidation at substantial rates, yielding both dopamine-4-O-glucuronide (37.1 pmol/min/mg) and dopamine-3-O-glucuronide (32.7 pmol/min/ mg). Much lower (<2 pmol/min/mg) or no dopamine glucuronidation activity was found for all other UGTs tested at 1 mM dopamine. Evaluation of the UGT1A10 expression pattern in human tissues by quantitative reverse transcription-polymerase chain reaction confirmed that it is mainly expressed in small intestine, colon, and adipose tissue, whereas only low levels were found in trachea, stomach, liver, testis, and prostate but not in brain. Dopamine glucuronidation assays using microsomes from human liver and intestine corroborated these findings because activity in intestinal microsomes was markedly higher than that in liver microsomes. Moreover, the glucuronidation regioselectivity in intestinal microsomes was similar to that of recombinant UGT1A10, and both enzyme sources exhibited sigmoidal kinetics with substrate affinity (K A ) values in the range of 2 to 3 mM. Examination of four UGT1A10 mutants, F90A, F90L, F93A, and F93L, revealed lower dopamine glucuronidation in all of them, particularly in F90A and F93A. Nonetheless, the substrate affinities of the four mutants were similar to that of UGT1A10. It is interesting to note that mutant F93L exhibited regioselectivity, conjugating dopamine at the 4-hydroxyl (OH) position approximately 3 times more efficiently than at the 3-OH position. These results shed new light on the structure and function of UGT1A10 and indicate that dopamine may be a useful probe substrate for this enzyme.

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“…In contrast, although enzyme activities were also enhanced by BNF, the activities decreased to control levels when administration had ceased. Elevated UGT activity, which is related to the metabolism of BaP (27), decreased when DBDE administration had ceased, although phase I enzyme activity was maintained after administration had ceased. This change in BaP metabolic enzymes appears to be related to the continuity of mutagenicity at high levels during the course of the experiment.…”

Section: Discussionmentioning

confidence: 99%

Effects of Oral Administration of Non-genotoxic Hepato-hypertrophic Compounds on Metabolic Potency of Rat Liver

Fang

Nunoshiba²,

Yoshida³

et al. 2014

Genes and Environment

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It remains uncertain why non-genotoxic compounds that result in liver hypertrophy cause liver tumors. In an eŠort to resolve this issue, we examined whether liver postmitochondrial fraction (S9) prepared from rats treated with non-genotoxic compounds aŠected the genotoxicity of pro-mutagens. Known hepatotoxic compounds, such as piperonyl butoxide (PBO), decabromodiphenyl ether (DBDE), beta-naphtho‰avone (BNF), indole-3-carbinol (I3C) and acetaminophen (AA), were orally administered to male and female F344 rats at doses su‹cient to cause liver hypertrophy. Rats received diets containing each test compound for 3 days, 4 weeks or 13 weeks, and were then kept for 4 weeks without the test chemical. S9 prepared from the livers of each group was used for the Ames test with 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), benzo[a]pyrene (BaP) and N-nitrosodimethylamine (NDMA). In both sexes, liver hypertrophy was observed following administration of all test compounds, and was then reversed to the control state when administration ceased. The mutagenicity of MeIQx, BaP and NDMA increased with the use of S9 derived from rats treated with non-genotoxic compounds other than AA. DBDE administration had a marked eŠect on the mutagenicity of BaP (over a 30-fold increase in females) and NDMA (about a 20-fold increase in males). To estimate the involvement of metabolic enzymes in the alteration of mutagenicity, we measured the activity of ethoxyresoruˆn-O-deethylase (EROD) and methoxyresoruˆn-O-demethylase (MROD) (phase I enzymes), and UDP-glucuronosyltransferase (UGT) and glutathione S-transferase (GST) (phase II enzymes) in each S9 sample. The activity of phase I enzymes increased, even at the 3rd day following administration, and then decreased gradually, except in the case of AA, while the activity of phase II enzymes increased slightly. These results suggest that non-genotoxic hepato-hypertrophic compounds may be partly involved in carcinogenesis by modulating the metabolism of pre-carcinogens incorporated from the environment, in a manner that is dependent on sex and pre-incorporated chemicals.

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Glucuronidation: An Important Mechanism for Detoxification of Benzo[a]Pyrene Metabolites in Aerodigestive Tract Tissues

Cited by 133 publications

References 28 publications

Pharmacogenomics of human UDP-glucuronosyltransferase enzymes

Pharmacogenomics of human UDP-glucuronosyltransferase enzymes

Dopamine Is a Low-Affinity and High-Specificity Substrate for the Human UDP-Glucuronosyltransferase 1A10

Effects of Oral Administration of Non-genotoxic Hepato-hypertrophic Compounds on Metabolic Potency of Rat Liver

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