Dose‐, route‐, and sex‐dependent urinary excretion of phenol metabolites in B6C3F1mice

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Abstract
Phenol is the major oxidized metabolite of benzene, a known human leukemogen and ubiquitous environmental pollutant. Unlike benzene, phenol does not induce tumors in mice following oral exposure; benzene also exhibits sex-related differences in genotoxicity to bone marrow cells that are not observed following phenol administration. We studied the urinary excretion of phenol metabolites in mice as a means to further investigate the metabolic basis for differences in benzene- and phenol-induced toxicity. Male and female B6C3F1 mice (n = 3/group) were exposed to 15, 40, 100, or 225 mumol [14C]phenol/kg by i.v. tail vein injection (6 microCi/mouse). First-pass intestinal metabolism of phenol was evaluated by comparison of urinary excretion of phenol metabolites following i.v. administration with additional groups of male mice that received the same dose levels by oral gavage. Mice were placed in glass metabolism cages, and urine was collected over dry ice for 48 h. Urinary metabolites were separated by high-pressure liquid chromatography (HPLC) and quantified by liquid scintillation spectrometry. Urinary excretion of conjugated metabolites of phenol was dose-dependent in both male and female mice administered phenol by i.v. injection or gavage. The major urinary metabolites of phenol were phenol sulfate (PS), phenol glucuronide (PG), and hydroquinone glucuronide (HQG). Sulfation was the dominant pathway at all dose levels, but decreased as a percent of the excreted dose with a concomitant increase in glucuronidation as the dose level increased. Male mice consistently excreted a higher proportion of phenol as the oxidized conjugated metabolite, HQG, compared to female mice, suggesting that male mice oxidize phenol to hydroquinone more rapidly than female mice. Increased oxidation of phenol to hydroquinone by male mice compared to female mice is consistent with both the greater sensitivity of male mice to the genotoxic effects of benzene and the greater potency of hydroquinone compared to phenol as a genotoxicant. Intestinal conjugation of phenol prior to absorption was significant only at low doses and thus alone does not provide an explanation for the lack of carcinogenicity of phenol in bioassays conducted at much higher dose levels.