The Glucuronidation of Exogenous and Endogenous Compounds by Stably Expressed Rat and Human UDP-Glucuronosyltransferase 1.1

King, Christopher D.; Green, Mitchell D.; Rios, Gladys R.; Coffman, Birgit L.; Owens, Ida S.; Bishop, Warren P.; Tephly, Thomas R.

doi:10.1006/abbi.1996.0320

Cited by 143 publications

(82 citation statements)

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“…BUP and N-BUP glucuronidation is mediated by UGT 1A1 (King et al, 1996), although apparently using a different active site than is used for bilirubin (Rios and Tephly, 2002). BUP and NBUP are also effectively glucuronidated by UGT 2B7 and 1A3, respectively (Y Chang and DE Moody, personal communication, Rios and Tephly, 2002).…”

Section: Discussionmentioning

confidence: 99%

Interaction between buprenorphine and atazanavir or atazanavir/ritonavir

McCance‐Katz

Moody

Morse

et al. 2007

Drug and Alcohol Dependence

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Opioid addiction and HIV disease frequently co-occur. Adverse drug interactions have been reported between methadone and some HIV medications, but less is known about interactions between buprenorphine, an opioid partial agonist used to treat opioid dependence, and HIV therapeutics. This study examined drug interactions between buprenorphine and the protease inhibitors atazanavir and atazanavir/ritonavir. Opioid-dependent, buprenorphine/naloxonemaintained, HIV-negative volunteers (n=10 per protease inhibitor) participated in two 24-hour sessions to determine pharmacokinetics of (1) buprenorphine and (2) buprenorphine and atazanavir (400 mg daily) or atazanavir/ritonavir (300/100 mg daily) following administration for 5 days. Objective opiate withdrawal scale scores and Mini-Mental State Examination were determined prior to and following antiretroviral administration to examine pharmacodynamic effects. Pharmacokinetics of atazanavir and atazanavir/ritonavir were compared in subjects and matched, healthy controls (n=10 per protease inhibitor) to determine effects of buprenorphine. With atazanavir and atazanavir/ritonavir, respectively concentrations of buprenorphine (p<0.001, p<0.001), norbuprenorphine (p=0.026, p=0.006), buprenorphine glucuronide (p=0.002, p<0.001), and norbuprenorphine glucuronide (NS, p=0.037) increased. Buprenorphine treatment did not significantly alter atazanavir or ritonavir concentrations. Three buprenorphine/naloxonemaintained participants reported increased sedation with atazanavir/ritonavir. Atazanavir or atazanavir/ritonavir may increase buprenorphine and buprenorphine metabolite concentrations and might require a decreased buprenorphine dose.

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Section: Discussionmentioning

confidence: 99%

Interaction between buprenorphine and atazanavir or atazanavir/ritonavir

McCance‐Katz

Moody

Morse

et al. 2007

Drug and Alcohol Dependence

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“…UGT1A1 has been most extensively studied due to its importance in clearing bilirubin. So far over 100 different substrates have been identified, including endogenous estrogens and numerous xenobiotic compounds, such as phenols and flavonoids [22][23][24]. A genetic polymorphism in the promotor region of UGT1A1, which contains an extra TA repeat (TA) 7 TAA instead of (TA) 6 TAA, results in reduced gene expression with concomitant reduction in enzyme activity [25][26][27].…”

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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“…Second, we report the regiospecificity of flavonoid glucuronidation by the 1A1 isozyme of human UDP-glucuronosyltransferase (UGT1A1). While there have been several studies on the glucuronidating activity of various isozymes of UGT using flavonoids as substrates [32][33][34][35][36][37][38], fewer have explored the regioselectivity of such reactions [19,39]. This report represents the first comprehensive assessment of the impact of the structural features of flavonoids on the enzymatic formation of flavonoid glucuronides.…”

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Regioselectivity of human UDP-glucuronosyl-transferase 1A1 in the synthesis of flavonoid glucuronides determined by metal complexation and tandem mass spectrometry

Davis

Brodbelt

2008

J. Am. Soc. Mass Spectrom.

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A three-part tandem mass spectrometric strategy that entails MS n analysis and a post-column LC-MS cobalt complexation method is developed to identify flavonoid monoglucuronide metabolites synthesized using the 1A1 isozyme of human UDP-glucuronosyltransferase (UGT). Ten flavonoid aglycons were used as substrates, spanning the subclasses of flavones, flavonols, and flavanones. The products were characterized by LC-MS and LC-MS n , with post-column cobalt complexation employed to pinpoint the specific sites of conjugation. The dissociation of complexes of the form [Co(II) (flavonoid glucuronide Ϫ H) (4,7-diphenyl-1,10-phenanthroline) 2 ] ϩ allowed identification of the products and differentiation of isomers. The correlation between glycosylation site and elution order is used to provide additional structural confirmation. Flavonoids lacking a 3= hydroxyl group were glucuronidated only at position 7, while those containing this functionality also formed 3=-O-glucuronides and sometimes 4=-O-glucuronides, thus supporting the conclusion that the presence or absence of the 3=-OH group is the major determinant of the regioselectivity of glucuronidation. Moreover, the specific distribution of multiple glucuronide products ( The currently accepted paradigm involves the consumption of flavonoid glycosides in plant-based food products, deglucosylation in the small intestine by ␤-glucosidase or lactose phloridzin hydrolase, and rapid metabolism by Phase I and (especially) Phase II enzymes [1][2][3]. Glucuronidation and sulfation are important metabolic routes for most flavonoids, while methylation or hydroxylation may also occur depending on the structure of the molecule in question [2,3]. There has also been a report of glutathionerelated metabolites in human urine [4]. As a result of these rapid conjugation reactions, neither the original flavonoid glycosides (except anthocyanins) nor the aglycon forms (except catechins) are found in plasma [5][6][7][8]. Early reports of unmodified flavonoid glycosides circulating in the bloodstream [9 -11] were likely mistaken identifications of flavonoid glucuronides, which have similar chromatographic and ultraviolet (UV) spectroscopic characteristics [7,12]. Flavonoids that fail to be absorbed in the small intestine may be broken down by microflora in the large intestine [1][2][3]. This process may release the free aglycons, which can then be absorbed and metabolized, but mostly results in the release of small phenolic acids, which are expelled in the urine [1][2][3]. Quantitative in vivo studies generally show that only a small percentage of consumed flavonoid glycosides is recovered in urine as conjugated Phase II metabolites [13][14][15]. Walle et al. used 14 Clabeled quercetin to show that up to 81% of the administered dose ultimately is exhaled in the form of carbon dioxide [16]. There remains considerable interest in the conjugated metabolites as they may retain some of the bioactivity of the original molecules [5,17].In spite of breakthroughs in the field of flavonoid metabol...

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The Glucuronidation of Exogenous and Endogenous Compounds by Stably Expressed Rat and Human UDP-Glucuronosyltransferase 1.1

Cited by 143 publications

References 0 publications

Interaction between buprenorphine and atazanavir or atazanavir/ritonavir

Interaction between buprenorphine and atazanavir or atazanavir/ritonavir

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

Regioselectivity of human UDP-glucuronosyl-transferase 1A1 in the synthesis of flavonoid glucuronides determined by metal complexation and tandem mass spectrometry

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