Decreased glucuronidation and increased bioactivation of acetaminophen in Gilbert's syndrome

Morais, S. M. F. De; Uetrecht, Jack; Wells, Peter G.

doi:10.1016/0016-5085(92)90106-9

Cited by 136 publications

(62 citation statements)

References 37 publications

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“…[119][120][121] Polymorphisms of the UGT1A1 Gene as Risk Factors for Drug-Induced Toxicity Patients affected by Gilbert's syndrome display lower glucuronidation rates for a number of therapeutic drugs including acetaminophen, tolbutamide and lorazepam. [20][21][22][34][35][36][37] Since Gilbert's syndrome is associated with the UGT1A1*28 (TA 7 polymorphism), it is more likely that patients with this allele will present an altered drug clearance compared to patients with the wild-type genotype. However, a correlation between the presence of variant UGT1A1 alleles and altered rates of glucuronidation has not been systematically demonstrated.…”

Section: Ugt1a1mentioning

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: Ugt1a1mentioning

confidence: 99%

Pharmacogenomics of human UDP-glucuronosyltransferase enzymes

2003

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“…20 Fasting is well-known to be associated with a decrease in the hepatic carbohydrate reserves 21 and in the activity of enzymes responsible for the production of uridine diphosphate-glucuronate, 22 leading to increased toxicity of acetaminophen in humans. Interestingly, patients with Gilbert' s syndrome appear to be more sensitive to acetaminophen than healthy subjects, 23 which supports this concept. Because the production of uridine diphosphate-glucuronate and glutathione are both reactions depending on the availability of energy in the form of adenosine triphosphate, it is conceivable that patients with cardiac failure could have a depletion of these substrates in zone III of the liver lobe, rendering them more sensitive to the toxic effects of acetaminophen.…”

mentioning

confidence: 73%

Acarbose and acetaminophen-a dangerous combination?

Krähenbühl¹

1999

Hepatology

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“…These deficiencies are responsible for Crigler-Najjar Type I and Type II syndromes as well as Gilbert's syndrome, a more common deficiency that affects more than 5% of the population (43). Impaired UGT activity can also result in enhanced drug toxicity (44); therefore, the significance of interindividual variability in human UGTs needs to be elucidated, a process that has been hampered by the limited availability of tissue.…”

Section: Discussionmentioning

confidence: 99%

Identification of Enzymes Responsible for the Metabolism of Heme in Human Platelets

Nowell¹,

Leakey²,

Warren³

et al. 1998

Journal of Biological Chemistry

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The major enzymes involved in the degradation of heme were identified in human platelets. It was determined that heme oxygenase activity levels in umbilical cord blood platelets were higher, whereas biliverdin reductase activity levels were comparable with that found in platelets from adults. In membranes prepared from adenosine diphosphate-activated platelets, UDP-glucuronic acid-dependent bilirubin conjugation was detected, whereas activity was negligible in unactivated platelets and undetected in serum and heat-inactivated platelets, and in platelets prepared from umbilical cord blood. Platelet fractions were analyzed by Western blot and shown to express heme oxygenase, biliverdin reductase, and UDP-glucuronosyltransferases, and there was concordance with known developmental profiles found in other tissues. Heme oxygenase expression was higher, whereas UGT expression was lower, in neonatal compared with adult platelets. These data suggest that platelets are involved in multiple steps of heme and bilirubin metabolism and that developmental regulation of these enzymes may be similar to that in other human tissues.

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Decreased glucuronidation and increased bioactivation of acetaminophen in Gilbert's syndrome

Cited by 136 publications

References 37 publications

Pharmacogenomics of human UDP-glucuronosyltransferase enzymes

Pharmacogenomics of human UDP-glucuronosyltransferase enzymes

Acarbose and acetaminophen-a dangerous combination?

Identification of Enzymes Responsible for the Metabolism of Heme in Human Platelets

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