Bilirubin and bile acids may modulate their own metabolism via regulating uridine diphosphate‐glucuronosyltransferase expression in the rat

Li, Yan Q.; Prentice, David; Howard, Monique L.; Mashford, Maurice L.; Desmond, Paul

doi:10.1046/j.1440-1746.2000.02223.x

Cited by 31 publications

(11 citation statements)

References 35 publications

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“…Our results did not show significantly different pharmacokinetic parameters in patients who had both UGT1A1 * 28 and UGT1A6 * 2 polymorphisms (group B) compared with group A. Li et al [34] suggested that bilirubin can induce the expression of UGTs. Hence, hyperbilirubinemia status in group B may play a compensatory role in modulating UGT expression and partly explain the evidence of no significantly lower PCM-G level in the patients who had both UGT1A1 * 28 and UGT1A6 * 2.…”

Section: Discussioncontrasting

confidence: 72%

Effects of Combined UDP-Glucuronosyltransferase (UGT) 1A128 and 1A62 on Paracetamol Pharmacokinetics in β-Thalassemia/HbE

Tankanitlert

Morales²,

Howard³

et al. 2006

Pharmacology

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In addition to pathophysiological changes, genetic variations can alter drug pharmacokinetics in patients with thalassemia. Numerous drugs are metabolized by UDP-glucuronosyltransferases (UGT) including paracetamol (PCM), a widely used analgesic. Co-occurrence of the UGT1A1 polymorphism (UGT1A1*28) and the UGT1A6 polymorphism (UGT1A6*2) may affect PCM glucuronidation. To elucidate the effect of these combined polymorphisms on the PCM metabolism in thalassemic patients, 15 β-thalassemia/hemoglobin E subjects with three different UGT1A genotypes received a single oral dose of 1,000 mg PCM. Drug disposition was determined by HPLC. Patients who have UGT1A6*2 without UGT1A1*28 showed a significant, lower area under concentration-time curve (AUC₀→∞) of PCM, PCM-glucuronide and PCM-sulfate than those of the patients with wild-type UGT1A1 and UGT1A6 (p < 0.05). In addition, a high elimination rate constant and clearance of PCM and its metabolites were also found in these patients (p < 0.05). Ourstudy suggests that a subtherapeutic level of PCM may occur in patients who have UGT1A6*2 without UGT1A1*28.

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Section: Discussioncontrasting

confidence: 72%

Effects of Combined UDP-Glucuronosyltransferase (UGT) 1A128 and 1A62 on Paracetamol Pharmacokinetics in β-Thalassemia/HbE

Tankanitlert

Morales²,

Howard³

et al. 2006

Pharmacology

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“…Only increased Calr and decreased Psmb4 were observed. Although effects from LCA on liver transcription are not well characterized, a previous study showed induction of UGT in primary rat hepatocytes exposed to LCA at a high concentration 100 mM for 48 h (Li et al, 2000). This type of change was not observed in this study.…”

Section: Drugs Not Directly Toxic To Hepatocytes In Vivo or Rarely Tocontrasting

confidence: 75%

In vitro gene expression analysis of hepatotoxic drugs in rat primary hepatocytes

Suzuki¹,

Inoue²,

Matsushita³

et al. 2008

J of Applied Toxicology

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The study examined the feasibility of screening for hepatotoxicity by an in vitro gene expression analysis using rat primary hepatocytes and Affymetrix Rat Toxicology U34 arrays. Hepatocytes were exposed for 6 or 24 h to eight drugs, with different mechanisms of hepatotoxicity, at one third of the cytotoxic concentration TC 50 , i.e. acetaminophen, cyclophosphamide, clofibrate, chlorpromazine, lithocholic acid, cisplatin, diclofenac and disulfiram. The types of transcriptional changes observed in this study were generally consistent with previously reported in vivo data, although there were some differences. In hierarchical cluster analysis, drugs formed clusters depending on their mode of toxicity against cells. The number of transcripts affected by the cholestatic hepatotoxicants (lithocholic acid and chlorpromazine) or the drugs that rarely cause of hepatotoxicity (cisplatin, diclofenac and disulfiram) were limited compared with the other drugs (acetaminophen, clobifibrate and cyclophosphamide), where they did not induce transcriptional changes apparently related to toxicity. It is concluded that in vitro gene expression analysis of hepatocytes using microarray is a useful tool for evaluating the toxicological profile of drugs and in screening for the direct toxicity of drugs against hepatocytes.

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“…Consequently, bilirubin induces activity of UGT1A1 (Li et al, 2000); and (2) the gestational hormones, such as progesterone and estrogens, decrease the maternal liver glucuronosyltransferase activity (Luquita et al, 2001). This could also affect the foetus during the gestational period.…”

Section: Discussionmentioning

confidence: 99%

Evolution of the activity of UGT1A1 throughout the development and adult life in a rat

et al. 2006

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Bilirubin and bile acids may modulate their own metabolism via regulating uridine diphosphate‐glucuronosyltransferase expression in the rat

Abstract: Our results suggest that bilirubin and bile acids can induce UGT expression and as a result, these compounds may modulate their own metabolism. Such regulation could play a compensatory role in the pathological increased concentrations of these compounds in some hepatobiliary diseases.

Cited by 31 publications

References 35 publications

Effects of Combined UDP-Glucuronosyltransferase (UGT) 1A128 and 1A62 on Paracetamol Pharmacokinetics in β-Thalassemia/HbE

Effects of Combined UDP-Glucuronosyltransferase (UGT) 1A128 and 1A62 on Paracetamol Pharmacokinetics in β-Thalassemia/HbE

In vitro gene expression analysis of hepatotoxic drugs in rat primary hepatocytes

Evolution of the activity of UGT1A1 throughout the development and adult life in a rat

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Bilirubin and bile acids may modulate their own metabolism via regulating uridine diphosphate‐glucuronosyltransferase expression in the rat

Abstract: Our results suggest that bilirubin and bile acids can induce UGT expression and as a result, these compounds may modulate their own metabolism. Such regulation could play a compensatory role in the pathological increased concentrations of these compounds in some hepatobiliary diseases.

Cited by 31 publications

References 35 publications

Effects of Combined UDP-Glucuronosyltransferase (UGT) 1A1*28 and 1A6*2 on Paracetamol Pharmacokinetics in β-Thalassemia/HbE

Effects of Combined UDP-Glucuronosyltransferase (UGT) 1A1*28 and 1A6*2 on Paracetamol Pharmacokinetics in β-Thalassemia/HbE

In vitro gene expression analysis of hepatotoxic drugs in rat primary hepatocytes

Evolution of the activity of UGT1A1 throughout the development and adult life in a rat

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Product

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Effects of Combined UDP-Glucuronosyltransferase (UGT) 1A128 and 1A62 on Paracetamol Pharmacokinetics in β-Thalassemia/HbE

Effects of Combined UDP-Glucuronosyltransferase (UGT) 1A128 and 1A62 on Paracetamol Pharmacokinetics in β-Thalassemia/HbE