Monitoring of cytochrome P-450 1A activity by determination of the urinary pattern of caffeine metabolites in Wistar and hyperbilirubinemic Gunn rats

Jorritsma, Ute; Schrader, Eberhard; Klaunick, Götz; Kapitulnik, Jaime; Hirsch‐Ernst, Karen Ildico; Kahl, Georg F.; Foth, Heidi

doi:10.1016/s0300-483x(99)00211-5

Cited by 15 publications

(4 citation statements)

References 30 publications

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“…After caffeine exposure, we evidenced paraxanthine metabolites only after 24 h of exposure. Paraxanthine provided from 3‐N demethylation of caffeine catalyzed by CYP1A2 and CYP2C11, the pivotal metabolism pathway of caffeine 31,32. RTqPCR analysis evidenced an upregulation of some PXR target genes, as CYP3A1 and CYP2C , all implicated in metabolism caffeine pathways,31,32 but we did not detect CYP1A2 induction.…”

Section: Discussioncontrasting

confidence: 54%

“…Paraxanthine provided from 3‐N demethylation of caffeine catalyzed by CYP1A2 and CYP2C11, the pivotal metabolism pathway of caffeine 31,32. RTqPCR analysis evidenced an upregulation of some PXR target genes, as CYP3A1 and CYP2C , all implicated in metabolism caffeine pathways,31,32 but we did not detect CYP1A2 induction. Further, liquid chromatography–mass spectrometry analyses need to be performed to detect other caffeine metabolites, as theobromine, theophylline, and 1,3,7‐trimethyluric acids and conclude on the kinetics of caffeine metabolism linked to CYP1A2 and 2C11 activities.…”

Section: Discussioncontrasting

confidence: 54%

See 1 more Smart Citation

Metabolic Characterization of Primary Rat Hepatocytes Cultivated in Parallel Microfluidic Biochips

Legendre

Baudoin

Alberto

et al. 2013

Journal of Pharmaceutical Sciences

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Section: Discussioncontrasting

confidence: 54%

Section: Discussioncontrasting

confidence: 54%

Metabolic Characterization of Primary Rat Hepatocytes Cultivated in Parallel Microfluidic Biochips

Legendre

Baudoin

Alberto

et al. 2013

Journal of Pharmaceutical Sciences

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“…Studies in jaundiced Gunn rat pups and then clinical trials of jaundiced newborns should be conducted to determine if: (1) induction of CYP1A1 (and possibly MRP1 [147]) with the nontoxic agent, indole‐3‐carbinol [148], can decrease accumulation of UCB in the plasma and tissues; and (2) treatment with ursodeoxycholate, which is protective against UCB‐induced apoptosis in cultured rat astrocytes and neurons [54], can protect jaundiced neonates from UCB toxicity. Additional prophylactic and therapeutic strategies may evolve, once many of the unresolved issues have been clarified by further studies.…”

Section: Discussionmentioning

confidence: 99%

New concepts in bilirubin encephalopathy

Ostrow¹,

Pascolo²,

Shapiro³

et al. 2003

Eur J Clin Investigation

138

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Revised concepts of bilirubin encephalopathy have been revealed by studies of bilirubin toxicity in cultured CNS cells and in congenitally jaundiced Gunn rats. Bilirubin neurotoxicity is related to the unbound (free) fraction of unconjugated bilirubin (B f ), of which the dominant species at physiological pH is the protonated diacid, which can passively diffuse across cell membranes. As the binding affinity of plasma albumin for bilirubin decreases strikingly as albumin concentration increases, previously reported B f values were underestimated. Newer diagnostic tests can detect reversible neurotoxicity before permanent damage occurs from precipitation of bilirubin (kernicterus). Early toxicity can occur at B f only modestly above aqueous saturation and affects astrocytes and neurons, causing mitochondrial damage, resulting in impaired energy metabolism and apoptosis, plus cell-membrane perturbation, which causes enzyme leakage and hampers transport of neurotransmitters.The concentrations of unbound bilirubin in the cerebro-spinal fluid and CNS cells are probably limited mainly by active export of bilirubin back into plasma, mediated by ABC transporters present in the brain capillary endothelium and choroid plexus epithelium. Intracellular bilirubin levels may be diminished also by oxidation, conjugation and binding to cytosolic proteins.These new concepts may explain the varied susceptibility of neonates to develop encephalopathy at any given plasma bilirubin level and the selective distribution of CNS lesions in bilirubin encephalopathy. They also can suggest better strategies for predicting, preventing and treating this syndrome.Keywords Bilirubin, jaundice, neonates, nuerotoxicity, encephalopathy, kernicterus. Abbreviations: BE, bilirubin encephalopathy; UCB, unconjugated bilirubin; BAEP, brainstem auditory evoked potentials; B f , free (unbound) fraction of UCB; HSA, human serum albumin; K f , affinity constant for binding of UCB to albumin; CSF, cerebrospinal fluid; BBB, blood-brain barrier; CP, choroid plexus. Eur J Clin Invest 2003; 33 ( 11): 988 -997

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“…Induction of cytochrome P450 1A (CYP1A) may be a valuable therapeutic modality for reducing the hyperbilirubinemia of infants with Crigler–Najjar syndrome type I (CNS‐I), a severe form of congenital jaundice. To evaluate inducers of CYP1A, a novel assay was established by Jorritsma et al (2000), based on the comparison of the type of urinary pattern of caffeine metabolites in rats when 10 mg/kg of 1‐Me‐14C‐caffeine is injected intraperitoneally before and 48 hr after injection of a potential CYP1A inducer, such as 5,6‐benzoflavone (BNF). The inducing effect of BNF on CYP1A activity was confirmed by the urinary pattern of caffeine metabolites in Wistar rats and was paralleled by a decrease in plasma bilirubin in male jj Gunn rats.…”

Section: Pharmacokineticsmentioning

confidence: 99%

Evaluation of the reproductive and developmental risks of caffeine

Brent

Christian

Diener

2011

Birth Defects Research Pt B

120

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A risk analysis of in utero caffeine exposure is presented utilizing epidemiological studies and animal studies dealing with congenital malformation, pregnancy loss, and weight reduction. These effects are of interest to teratologists, because animal studies are useful in their evaluation. Many of the epidemiology studies did not evaluate the impact of the “pregnancy signal,” which identifies healthy pregnancies and permits investigators to identify subjects with low pregnancy risks. The spontaneous abortion epidemiology studies were inconsistent and the majority did not consider the confounding introduced by not considering the pregnancy signal. The animal studies do not support the concept that caffeine is an abortafacient for the wide range of human caffeine exposures. Almost all the congenital malformation epidemiology studies were negative. Animal pharmacokinetic studies indicate that the teratogenic plasma level of caffeine has to reach or exceed 60 µg/ml, which is not attainable from ingesting large amounts of caffeine in foods and beverages. No epidemiological study described the “caffeine teratogenic syndrome.” Six of the 17 recent epidemiology studies dealing with the risk of caffeine and fetal weight reduction were negative. Seven of the positive studies had growth reductions that were clinically insignificant and none of the studies cited the animal literature. Analysis of caffeine's reproductive toxicity considers reproducibility and plausibility of clinical, epidemiological, and animal data. Moderate or even high amounts of beverages and foods containing caffeine do not increase the risks of congenital malformations, miscarriage or growth retardation. Pharmacokinetic studies markedly improve the ability to perform the risk analyses. Birth Defects Res (Part B) 92:152–187, 2011. © 2011 Wiley-Liss, Inc.

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Monitoring of cytochrome P-450 1A activity by determination of the urinary pattern of caffeine metabolites in Wistar and hyperbilirubinemic Gunn rats

Cited by 15 publications

References 30 publications

Metabolic Characterization of Primary Rat Hepatocytes Cultivated in Parallel Microfluidic Biochips

Metabolic Characterization of Primary Rat Hepatocytes Cultivated in Parallel Microfluidic Biochips

New concepts in bilirubin encephalopathy

Evaluation of the reproductive and developmental risks of caffeine

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