Tissue distribution and plasma protein binding of [14C]phenol in rats

Liao, Teh Fang

doi:10.1016/0041-008x(81)90282-9

Cited by 17 publications

(4 citation statements)

References 13 publications

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“…The phenol lead series, including BI-3231 , showed a strong NAD + dependency for binding and inhibition of HSD17B13. BI-3231 was investigated in pharmacokinetic studies revealing a disconnect between in vitro and in vivo clearance while showing extensive liver tissue accumulation . We note that pronounced phase II metabolic biotransformation may limit its use in metabolically competent systems.…”

Section: Discussionmentioning

confidence: 99%

“…BI-3231 was investigated in pharmacokinetic studies revealing a disconnect between in vitro and in vivo clearance while showing extensive liver tissue accumulation. 72 We note that pronounced phase II metabolic biotransformation may limit its use in metabolically competent systems. Nonetheless, due to its improved overall profile, we suggest the well-characterized specific HSD17B13 inhibitor BI-3231 as a valuable chemical probe to further elucidate the biological function of HSD17B13.…”

Section: Discussionmentioning

confidence: 99%

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Discovery of a Novel Potent and Selective HSD17B13 Inhibitor, BI-3231, a Well-Characterized Chemical Probe Available for Open Science

et al. 2023

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Genome-wide association studies in patients revealed HSD17B13 as a potential new target for the treatment of nonalcoholic steatohepatitis (NASH) and other liver diseases. However, the physiological function and the disease-relevant substrate of HSD17B13 remain unknown. In addition, no suitable chemical probe for HSD17B13 has been published yet. Herein, we report the identification of the novel potent and selective HSD17B13 inhibitor BI-3231. Through high-throughput screening (HTS), using estradiol as substrate, compound 1 was identified and selected for subsequent optimization resulting in compound 45 (BI-3231). In addition to the characterization of compound 45 for its functional, physicochemical, and drug metabolism and pharmacokinetic (DMPK) properties, NAD + dependency was investigated. To support Open Science, the chemical HSD17B13 probe BI-3231 will be available to the scientific community for free via the opnMe platform, and thus can help to elucidate the pharmacology of HSD17B13.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Discovery of a Novel Potent and Selective HSD17B13 Inhibitor, BI-3231, a Well-Characterized Chemical Probe Available for Open Science

et al. 2023

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“…For example, the proportions of phenol bound to dog and rat plasma were estimated to be about 50% and 60%, respectively (Liao and Oehme 1981). The more acidic pentachlorophenol shows even a higher degree of binding (>99%) to rat plasma proteins (Schmieder and Henry 1988).…”

Section: Unspecific Protein Bindingmentioning

confidence: 99%

Distribution and unspecific protein binding of the xenoestrogens bisphenol A and daidzein

Csanády

Oberste-Frielinghaus

Semder

et al. 2002

Archives of Toxicology

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Physiological toxicokinetic (PT) models are used to simulate tissue burdens by chemicals in animals and humans. A prerequisite for a PT model is the knowledge of the chemical's distribution among tissues. This depends on the blood flow and also on the free fraction of the substance and its tissue:blood partition coefficients. In the present study we determined partition coefficients in human tissues at 37 degrees C for the two selected xenoestrogens bisphenol A (BA) and daidzein (DA), and their unspecific binding to human serum proteins. Partition coefficients were obtained by incubating blood containing BA or DA with each of the following tissues: brain, liver, kidney, muscle, fat, placenta, mammary gland, and adrenal gland. Blood samples were analysed by HPLC. For BA and DA, all partition coefficients in non-adipose tissues were similar (average values: BA 1.4, DA 1.2). However, the lipophilic properties of both compounds diverge distinctly. Fat:blood partition coefficients were 3.3 (BA) and 0.3 (DA). These values indicate that with the exception of fat both compounds are distributed almost equally among tissues. In dialysis experiments, the unspecific binding of BA and DA with human serum proteins was measured by HPLC. For BA, the total concentration of binding sites and the apparent dissociation constant were calculated as 2000 and 100 nmol/ml, respectively. Because of the limited solubility of DA, only the ratio of the bound to the free DA concentration could be determined and was found to be 7.2. These values indicate that at low concentrations only small percentages of about 5% (BA) and 12% (DA) are as unbound free fractions in plasma. Since only the unbound fraction can bind to the estrogen receptor, binding to serum proteins represents a mechanism that limits the biological response in target tissues.

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“…Once absorbed, phenol is rapidly distributed to all tissues in animals; within 15 min of an oral dose, the highest concentrations are found in the liver, followed by the heart, kidneys, lungs, blood, and muscle (Deichmann, 1944; Table 2). Additional studies on rats demonstrated that the liver, spleen, kidney, and adrenal gland consistently exhibited phenol concentrations greater than those observed in plasma (Liao and Oehme, 1981). Elevated levels of 14 C-phenol (phenol plus metabolites) were also found in the thyroid glands and the lungs compared to the plasma.…”

Section: Health Effectsmentioning

confidence: 91%

Summary Review of the Health Effects Associated With Phenol

1987

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Phenol, a monohydroxy derivative of benzene, occurs naturally in animal waste and by decomposition of organic wastes. It is also produced by man, originally by fractional distillation of coal tar, but more recently by cumene hydroperoxidation and toluene oxidation. As a result of large production volume and natural sources, occupational and environmental exposure to phenol is likely. Phenol poisoning can occur by skin absorption, vapor inhalation, or ingestion, and, regardless of route of exposure, can result in detrimental health effects. Acute toxicity has been observed in man and experimental animals, resulting in muscle weakness, convulsions, and coma. In addition, studies have shown that although teratogenic effects have not been associated with exposure to phenol by either inhalation or oral route, high doses of phenol are fetotoxic. This paper addresses these studies and others in an attempt to determine if human health is at risk to those levels of phenol present in the environment and workplace. However, because data are limited, further research is necessary to analyze the mutagenic and carcinogenic potential of this chemical.

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Tissue distribution and plasma protein binding of [14C]phenol in rats

Cited by 17 publications

References 13 publications

Discovery of a Novel Potent and Selective HSD17B13 Inhibitor, BI-3231, a Well-Characterized Chemical Probe Available for Open Science

Discovery of a Novel Potent and Selective HSD17B13 Inhibitor, BI-3231, a Well-Characterized Chemical Probe Available for Open Science

Distribution and unspecific protein binding of the xenoestrogens bisphenol A and daidzein

Summary Review of the Health Effects Associated With Phenol

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