Genetic polymorphisms of UDP-glucuronosyltransferases and their functional significance

Miners, John O.; McKinnon, Ross A.; Mackenzie, Peter I.

doi:10.1016/s0300-483x(02)00449-3

Cited by 183 publications

(134 citation statements)

References 16 publications

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“…UGT1A degrades the majority of toxins and carcinogens (10). Amines in epithelial cells may be further activated to form DNA adducts, which in turn activate the carcinogenic process by gene mutation.…”

Section: Discussionmentioning

confidence: 99%

Expression of UDP-glucuronosyltransferase 1A, nuclear factor erythroid-E2-related factor 2 and Kelch-like ECH-associated protein 1 in colonic mucosa, adenoma and adenocarcinoma tissue

Wang

Chen

et al. 2012

Oncology Letters

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Section: Discussionmentioning

confidence: 99%

Expression of UDP-glucuronosyltransferase 1A, nuclear factor erythroid-E2-related factor 2 and Kelch-like ECH-associated protein 1 in colonic mucosa, adenoma and adenocarcinoma tissue

Wang

Chen

et al. 2012

Oncology Letters

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“…Recently, functional polymorphisms in the genes encoding the various UGT1 family members have been discovered [18][19][20][21]. UGT1A1 has been most extensively studied due to its importance in clearing bilirubin.…”

Section: Introductionmentioning

confidence: 99%

Functional polymorphisms of UDP-glucuronosyltransferases 1A1, 1A6 and 1A8 are not involved in chronic pancreatitis

Verlaan

Morsche

Pap³

et al. 2004

Pharmacogenetics

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aObjectives Chronic pancreatitis (CP) is associated with alcohol abuse, smoking and other dietary or environmental factors. UDP-glucuronosyltransferases (UGTs) are phase II detoxifying enzymes responsible for glucuronidation of various exogenous and endogenous compounds. Genetic variations, resulting in variable rates of glucuronidation, are of toxicological and physiological importance and are frequently associated with diseases. Recently, a genetic polymorphism in UGT1A7 was possibly associated with an increased risk for CP. We investigated whether polymorphisms in the genes for UGT1A1, UGT1A6 and UGT1A8 modified the risk for CP.Methods DNA samples were obtained from 258 adult CP patients with alcoholic (n 153), hereditary (n 25) or idiopathic (n 80) origin. DNA from 140 healthy controls was analyzed for comparison. Patients and controls were all of Caucasian origin. Genetic polymorphisms in UGTs were determined by PCR, eventually followed by restriction-fragment-length-polymorphism analyses in all subjects.Results The distribution of the various alleles of UGT1A1, UGT1A6 and UGT1A8 did not differ between CP patients and healthy controls.Conclusion These data suggest that genetic polymorphisms in UGT1A1, UGT1A6 and in UGT1A8 do not predispose to the development of CP in Caucasians.

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“…26,29) Genetic polymorphism has been reported for UGT1A1 and other isoforms. 26,30,31) In this study, we could not obtain the genotype information of liver donors. Therefore, we did not evaluate the possible contribution of UGT polymorphisms to the variability in the catalytic activity of EE 2 3-glucuronidation in this study.…”

Section: Discussionmentioning

confidence: 99%

Interindividual Variability in 2-Hydroxylation, 3-Sulfation, and 3-Glucuronidation of Ethynylestradiol in Human Liver

Shiraga

Niwa

Ohno

et al. 2004

Biological & Pharmaceutical Bulletin

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Ethynylestradiol (EE 2 ) is commonly used as the major estrogenic component in many oral contraceptive formulations. Orme et al. 1) reported that EE 2 is metabolized by multiple pathways, and there is a large interindividual variability in the routes and rates of metabolism of EE 2 in humans. In addition, marked interindividual differences in the pharmacokinetic parameters of EE 2 have been reported.1) The reported systemic bioavailability of orally ingested EE 2 ranges from 20 to 65%. 1) Factors that could affect oral clearance of a drug include absorption from the gastrointestinal tract, protein binding, intrinsic hepatic clearance, hepatic blood flow, and renal clearance. Urinary excretion of unchanged EE 2 was very low, 2) suggesting that EE 2 is mainly eliminated by metabolism. The 2-hydroxylation of EE 2 is mainly catalyzed by CYP3A, CYP2C, and CYP2E enzymes, 3,4) and this route is one of the main metabolic pathways in humans.5,6) Additionally, sulfation and glucuronidation also play important roles in the metabolism of EE 2 . EE 2 -3-glucuronide and EE 2 -3-sulfate are eliminated into the gastrointestinal tract, hydrolyzed by gut bacteria to EE 2 , and subsequently reabsorbed. Rifampicin, an inducer of CYP3A, has been reported to significantly increase the oral clearance of EE 2 .7) This interaction is thought to reflect the significant contribution of CYP3A enzymes to the metabolism of EE 2 . It is well known that there are large interindividual differences in the expression levels and catalytic activities of CYP3A enzymes in human liver. 8)Patki et al. 9) indicated that the intrinsic clearance of triazolam, a CYP3A substrate, and CYP3A protein in human liver are reduced in the elderly.In vitro studies are useful for clarifying the role of respective enzymes on the systemic drug clearance. Plasma concentrations of EE 2 achieved during normal therapy are very low (Ͻ2 nM).7) However, most previous in vitro studies used substantially high EE 2 substrate concentrations (Ͼ10 mM). A recent study using human hepatocytes in vitro at a substrate concentration of 1 nM demonstrated that the major EE 2 metabolites are direct conjugates, with hydroxylation representing minor pathways, and suggested that the production of EE 2 -3-sulfate was increased by pretreatment of hepatocytes with rifampicin.10) The initial rate of conjugate formation was reported to be EE 2 -3-sulfateϾEE 2 -3-glucuronide in human hepatocytes. 10) In the current study, we investigated interindividual variability of the 2-hydroxylation, 3-glucuronidation, and 3-sulfation of EE 2 using human liver microsomes and cytosol in the presence of the respective cofactors. Additionally, interindividual variability of the relative contribution of CYP3A to the 2-hydroxylation of EE 2 in human liver microsomes was estimated from the degree of inhibition by ketoconazole, a potent inhibitor of CYP3A. All enzyme activities were measured at an EE 2 substrate concentration of 0.1 mM, which is under a nearly linear condition (Ͻ1/23 of K m values for the respectiv...

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Genetic polymorphisms of UDP-glucuronosyltransferases and their functional significance

Cited by 183 publications

References 16 publications

Expression of UDP-glucuronosyltransferase 1A, nuclear factor erythroid-E2-related factor 2 and Kelch-like ECH-associated protein 1 in colonic mucosa, adenoma and adenocarcinoma tissue

Expression of UDP-glucuronosyltransferase 1A, nuclear factor erythroid-E2-related factor 2 and Kelch-like ECH-associated protein 1 in colonic mucosa, adenoma and adenocarcinoma tissue

Functional polymorphisms of UDP-glucuronosyltransferases 1A1, 1A6 and 1A8 are not involved in chronic pancreatitis

Interindividual Variability in 2-Hydroxylation, 3-Sulfation, and 3-Glucuronidation of Ethynylestradiol in Human Liver

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