Quantitative analysis of cresol and its metabolites in biological materials and distribution in rats after oral administration

Morinaga, Yasumasa; Fuke, Chiaki; Arao, Tomonori; Miyazaki, Tetsuji

doi:10.1016/j.legalmed.2003.08.005

Cited by 22 publications

(19 citation statements)

References 8 publications

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“…Specifically, after oral dosing 63.4 ± 2.3% was excreted as phenyl sulphate and 26.8 ± 2.7% was excreted as phenyl glucuronides. Similar findings are reported for methylphenols [11].…”

Section: Toxicokinetic Differencessupporting

confidence: 90%

“…Morinaga et al reported on the toxicokinetics of an oral-administered cresol soap solution containing 3-methyl-and 4-methylphenol [11]. In Wister rats, the phenols were readily absorbed, distributed throughout the body, eliminated, for the most part, within several hours and excreted mainly as glucuronide and sulphate metabolites.…”

Section: Similarities In Toxicokinetics Of Mono-alkylphenolsmentioning

confidence: 99%

See 1 more Smart Citation

Read-across for rat oral gavage repeated-dose toxicity for short-chain mono-alkylphenols: A case study

Mellor

Schultz

Przybylak

et al. 2017

Computational Toxicology

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Short-chain mono-alkylphenols provide an example of where a category-approach to read-across may be used to estimate the repeated-dose endpoint for a number of derivatives. Specifically, the NOAELs of 50 mg/kg bw/d for mono-methylphenols based on a LOAEL of very low systemic toxicity can be read across with confidence to untested mono-alkylphenols in the category. These simple alkylphenols are non-reactive and exhibit an unspecific, reversible polar narcosis mode of toxic action. Briefly, polar narcotics act via unspecific, reversible interactions with biological membranes in a manner similar to cataleptic anaesthetics. The readacross premise includes rapid and complete absorption via the gastrointestinal tract, distribution in the circulatory system, first-pass Phase 2 metabolism in the liver, and elimination of sulphates 3 and glucuronides in the urine. Thus, toxicokinetic parameters are considered to be similar and have the same toxicological significance. Five analogues have high quality experimental oral repeated-dose toxicity data (i.e., OECD TG 408 or OECD TG 422). These repeated-dose toxicity test results exhibit qualitative consistency in symptoms. Typical findings include decreased body weight and slightly increased liver and kidney weights which are generally without concurrent histopathological effects. The sub-chronic findings are quantitatively consistent with the No Observed Adverse Effect Level (NOAEL) of ≥ 50 mg/kg bw/d. Chemical similarity between the analogues is readily defined, and data uncertainty associated with the similarities in toxicokinetic properties, as well as toxicodynamic properties, are low. Uncertainty associated with mechanistic relevance and completeness of the read-across is lowto-moderate, largely because there is no adverse outcome pathway or intermediate event data. Uncertainty associated with mechanistic relevance and completeness of the read-across is reduced by the concordance of in vivo, in vitro, USEPA toxicity forecaster (ToxCast) results, as well as the in silico data. The rat oral repeated-dose NOAEL values for the source substances can be read across to fill the data gaps of the untested analogues in this category with uncertainty deemed equivalent to results from a TG 408 assessment. .

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“…Specifically, after oral dosing 63.4 ± 2.3% was excreted as phenyl sulphate and 26.8 ± 2.7% was excreted as phenyl glucuronides. Similar findings are reported for methylphenols [11].…”

Section: Toxicokinetic Differencessupporting

confidence: 90%

Section: Similarities In Toxicokinetics Of Mono-alkylphenolsmentioning

confidence: 99%

Read-across for rat oral gavage repeated-dose toxicity for short-chain mono-alkylphenols: A case study

Mellor

Schultz

Przybylak

et al. 2017

Computational Toxicology

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“…Thus, in the present context, it is particularly notable that p-cresol and acetaminophen are both substrates for the same human cytosolic sulfotransferase, SULT1A1 (26), and can, therefore, compete for enzyme binding sites as well as for PAPS. Furthermore, in contrast to what has been reported for rats (27), recent literature suggests that p-cresol is almost entirely converted to PCS in humans (28)(29)(30) capacity to sulfonate acetaminophen will be reduced by ongoing presentation of endogenous p-cresol, and the potential competitive significance of the p-cresol challenge was confirmed by calculation (SI Text). On the basis of this hypothesis, we examined, with the full data set, the postdose excretion of both S and G and found that, in the 3-6 h collection, the high predose PCS subjects (I.R.…”

Section: Resultsmentioning

confidence: 76%

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.

693

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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“…p -Cresol forms endogenously from metabolism of tyrosine by gut microflora (Bone et al, 1976). In rats, m and p cresols administered by gavage were absorbed, detected in blood, and distributed to major tissues such as brain, kidney, liver, lung, muscle, and spleen (Morinaga et al, 2004). Cresols primarily are conjugated to glucuronic acid or undergo sulfation and are excreted in urine of rabbits, rats, and humans (Williams, 1938; Bray et al, 1950; Ogata et al, 1995; Lesaffer et al, 2003; Morinaga et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…In rats, m and p cresols administered by gavage were absorbed, detected in blood, and distributed to major tissues such as brain, kidney, liver, lung, muscle, and spleen (Morinaga et al, 2004). Cresols primarily are conjugated to glucuronic acid or undergo sulfation and are excreted in urine of rabbits, rats, and humans (Williams, 1938; Bray et al, 1950; Ogata et al, 1995; Lesaffer et al, 2003; Morinaga et al, 2004). p -Cresol may be metabolized through reactive pathways as indicated by detection of p -hydroxybenzoic acid in the urine of p -cresol-dosed rabbits (Bray et al, 1950) and p -cresol-derived glutathione conjugates in rat or human microsomal preparations (Thompson et al, 1995; Yan et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Carcinogenesis studies of cresols in rats and mice

et al. 2009

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Cresols, monomethyl derivatives of phenol, are high production chemicals with potential for human exposure. The three isomeric forms of cresol are used individually or in mixtures as disinfectants, preservatives, and solvents or as intermediates in the production of antioxidants, fragrances, herbicides, insecticides, dyes, and explosives. Carcinogenesis studies were conducted in groups of 50 male F344/N rats and 50 female B6C3F1 mice exposed to a 60:40 mixture of m and p cresols (m-/p-cresol) in feed. Rats and mice were fed diets containing 0, 1500, 5000, or 15,000 ppm and 0, 1000, 3000, or 10,000 ppm, respectively. Survival of each exposed group was similar to that of their respective control group. Mean body weight gains were depressed in rats exposed to 15,000 ppm and in mice exposed to 3000 ppm and higher. A decrease of 25% over that of controls for the final mean body weight in mice exposed to 10,000 ppm appeared to be associated with lack of palatability of the feed. A marginally increased incidence of renal tubule adenoma was observed in the 15,000 ppm-exposed rats. The increased incidence was not statistically significant, but did exceed the range of historical controls. No increased incidence of hyperplasia of the renal tubules was observed; however, a significantly increased incidence of hyperplasia of the transitional epithelium associated with an increased incidence of nephropathy was observed at the high exposure concentration. The only significantly increased incidence of a neoplastic lesion related to cresol exposure observed in these studies was that of squamous cell papilloma in the forestomach of 10,000 ppm-exposed mice. A definitive association with irritation at the site-of-contact could not be made because of limited evidence of injury to the gastric mucosa at the time of necropsy. However, given the minimal chemical-related neoplastic response in these studies, it was concluded that there was no clear evidence of carcinogenicity in male rats or female mice exposed to the cresol mixture.

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Quantitative analysis of cresol and its metabolites in biological materials and distribution in rats after oral administration

Cited by 22 publications

References 8 publications

Read-across for rat oral gavage repeated-dose toxicity for short-chain mono-alkylphenols: A case study

Read-across for rat oral gavage repeated-dose toxicity for short-chain mono-alkylphenols: A case study

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

Carcinogenesis studies of cresols in rats and mice

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