Cresol Isomers: Comparison of Toxic Potency in Rat Liver Slices

Thompson, D. C.; Perera, Kumar; Fisher, Ron; Brendel, Klaus

doi:10.1006/taap.1994.1048

Cited by 77 publications

(50 citation statements)

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“…We envisage that, by depleting hepatic sulfonation capacity, continual exposure to colonically produced p-cresol would leave the liver more vulnerable to acetaminophen-induced damage and that markedly increased p-cresol production could potentially explain the reported association between fasting and an increased likelihood of hepatotoxicity from acetaminophen (42,43). However, in principle, sustained prior exposure to colonically produced p-cresol could also potentially increase acetaminophen hepatotoxicity by other means, such as by enzyme induction or glutathione depletion (44)(45)(46), and preliminary data (SI Text) suggest that high p-cresol exposure might lead to a more generalized impairment of sulfurdependent reactive metabolite detoxification, with PAPS depletion possibly leading to depletion of both taurine and glutathione. However, it remains to be investigated if our present finding has any significance for adverse reactions to acetaminophen.…”

Section: Resultsmentioning

confidence: 99%

Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism

Clayton

Baker

Lindon

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

697

573

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We provide a demonstration in humans of the principle of pharmacometabonomics by showing a clear connection between an individual's metabolic phenotype, in the form of a predose urinary metabolite profile, and the metabolic fate of a standard dose of the widely used analgesic acetaminophen. Predose and postdose urinary metabolite profiles were determined by 1 H NMR spectroscopy. The predose spectra were statistically analyzed in relation to drug metabolite excretion to detect predose biomarkers of drug fate and a human-gut microbiome cometabolite predictor was identified. Thus, we found that individuals having high predose urinary levels of p-cresol sulfate had low postdose urinary ratios of acetaminophen sulfate to acetaminophen glucuronide. We conclude that, in individuals with high bacterially mediated p-cresol generation, competitive O-sulfonation of p-cresol reduces the effective systemic capacity to sulfonate acetaminophen. Given that acetaminophen is such a widely used and seemingly well-understood drug, this finding provides a clear demonstration of the immense potential and power of the pharmacometabonomic approach. However, we expect many other sulfonation reactions to be similarly affected by competition with p-cresol and our finding also has important implications for certain diseases as well as for the variable responses induced by many different drugs and xenobiotics. We propose that assessing the effects of microbiome activity should be an integral part of pharmaceutical development and of personalized health care. Furthermore, we envisage that gut bacterial populations might be deliberately manipulated to improve drug efficacy and to reduce adverse drug reactions.T he effects of drug treatments can vary greatly between different individuals, and pharmacogenomics has been widely advocated as a potential means of personalizing human drug treatments to increase drug efficacy and to decrease adverse reactions (1-6). However, environmental factors (such as nutritional status, gut bacterial activities, age, disease, and other drug use) are also important determinants of individual metabolic phenotypes, which modulate drug metabolism, efficacy, and toxicity. Such environmental complications, which may also alter gene expression, will tend to limit the usefulness of predictions of drug-induced responses that are based only on genomic differences (7,8). For instance, for many classes of compound, enzyme induction state, which is environmentally determined, influences drug metabolism and toxicity and this is not captured in genomic data. Recognizing this important limitation of pharmacogenomics, a different approach to personalized drug treatment has recently been proposed wherein predose metabolite profiling would instead be used to predict a subject's responses to potential drug interventions (9). This ''pharmacometabonomic'' approach has a number of major advantages, which include the ready availability and relative ease of analysis of biofluids, such as urine and blood plasma, as well as the fact that ...

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Section: Resultsmentioning

confidence: 99%

Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism

Clayton

Baker

Lindon

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

697

573

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“…Because p-cresol competes with drugs for protein binding, it can substantially enhance the toxic effect of uremia (Lesaffer et al, 2001). In vitro studies have suggested a potential association between hepatotoxicity and metabolic activation of p-cresol (Thompson et al, 1994(Thompson et al, , 1995, although such a relationship remains to be established in vivo.…”

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confidence: 99%

Bioactivation of 4-Methylphenol (p-cresol) via CYP-mediated Aromatic Oxidation in Human Liver Microsomes

Yan¹

2005

Drug Metabolism and Disposition

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ABSTRACT:It has previously been proposed that 4-methylphenol (p-cresol) is metabolically activated by oxidation of the methyl group to form a reactive quinone methide. In the present study a new metabolism pathway is elucidated in human liver microsomes. Oxidation of the aromatic ring leads to formation of 4-methyl-ortho-hydroquinone, which is further oxidized to a reactive intermediate, 4-methylortho-benzoquinone. This bioactivation pathway is fully supported by the following observations: 1) one major and two minor glutathione (GSH) adducts were detected in microsomal incubations of p-cresol in the presence of glutathione; 2) a major metabolite of p-cresol was identified as 4-methyl-ortho-hydroquinone in microsomal incubations; 3) the same GSH adducts were detected in microsomal incubations of 4-methyl-ortho-hydroquinone; and 4) the same GSH adducts were chemically synthesized by oxidizing 4-methyl-ortho-hydroquinone followed by the addition of GSH, and the major conjugate was identified by liquid chromatography-tandem mass spectrometry and NMR as 3-(glutathione-S-yl)-5-methyl-ortho-hydroquinone. In addition, it was found that 4-hydroxybenzylalcohol, a major metabolite derived from oxidation of the methyl group in liver microsomes, was further converted to 4-hydroxybenzaldehyde. In vitro studies also revealed that bioactivation of p-cresol was mediated by multiple cytochromes P450, but CYP2D6, 2E1, and 1A2 are the most active enzymes for formation of quinone methide, 4-methyl-ortho-benzoquinone, and 4-hydroxybenzaldehyde, respectively. Implications of the newly identified reactive metabolite in p-cresol-induced toxicity remain to be investigated in the future.

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“…Further, from the data by Thompson et al, (1994), the involvement of a quinone-hydroquinone redox cycle in hepatocellular GSH depletion by 2-and 3-methylphenol cannot be excluded.…”

Section: Ester Hydrolysismentioning

confidence: 97%

“…Despite the fact that 2-and 3-methylphenols are considerably less cytotoxic than the p-isomer, also with 2-and 3-methylphenol some decrease of hepato-cellular GSH has been observed, which could indicate the involvement of an epoxide in the metabolism towards 2,5-dihydroxytoluene (Bray et al, 1950a;Thompson et al, 1994). Further, from the data by Thompson et al, (1994), the involvement of a quinone-hydroquinone redox cycle in hepatocellular GSH depletion by 2-and 3-methylphenol cannot be excluded.…”

Section: Ester Hydrolysismentioning

confidence: 99%

“…In both cases this is reflected in lower cytotoxicity of the respective parent phenol (Thompson et al, 1995b). If concentrations of the quinone methide intermediates are insufficient to deplete intracellular GSH, they may be detoxicated via conjugation with this scavenger (Thompson et al, 1994;Thompson et al, 1995a;Thompson et al, 1995b). No data have been submitted to describe or support the metabolism of 2,6-dimethoxy- .061] with respect to the vinyl ring substituent.…”

Section: Ester Hydrolysismentioning

confidence: 99%

See 1 more Smart Citation

Scientific Opinion on Flavouring Group Evaluation 22, Revision 1 (FGE.22Rev1): Ring‐substituted phenolic substances from chemical groups 21 and 25

Flavourings¹

2011

EFS2

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The Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids of the European Food Safety Authority was requested to evaluate 28 flavouring substances in the Flavouring Group Evaluation 22, Revision 1, using the Procedure in Commission Regulation (EC) No 1565/2000. The substance 3,4-methylenedioxyphenol [FL-no: 04.080] was reported to have a genotoxic potential in vitro, while in vivo studies were not available. Therefore, the Panel concluded that the Procedure could not be applied to this substance until adequate genotoxicity data become available. The remaining 27 substances were evaluated through a stepwise approach (the Procedure) that integrates information on structure-activity relationships, intake from current uses, toxicological threshold of concern, and available data on metabolism and toxicity. The Panel concluded that these 27 candidate substances do not give rise to safety concerns at their levels of dietary intake, estimated on the basis of the MSDI approach. Adequate specifications for the materials of commerce are available for all 27 flavouring substances evaluated through the Procedure.

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Cresol Isomers: Comparison of Toxic Potency in Rat Liver Slices

Cited by 77 publications

References 0 publications

Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism

Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism

Bioactivation of 4-Methylphenol (p-cresol) via CYP-mediated Aromatic Oxidation in Human Liver Microsomes

Scientific Opinion on Flavouring Group Evaluation 22, Revision 1 (FGE.22Rev1): Ring‐substituted phenolic substances from chemical groups 21 and 25

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