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Disposition and Metabolism of Aniline in Fischer 344 Rats and C57BL/6 x C3H F₁ Mice¹

Kettering-Meyer Laboratory, Southern Research Institute, Birmingham, Alabama 35255

We examined the metabolism and disposition of aniline, which induces spleen hemangiosarcomas in rats but no tumors in mice, in normal and predosed Fischer 344 rats, and C57BL/6 x C3H F₁ mice administered low (50 and 100 mg/kg, respectively) or high (250 and 500 mg/kg, respectively) doses. Of 11 tissues examined, the highest levels of binding of [¹⁴C]aniline to DNA were in the kidney, large intestine, and spleen of high-dose rats that had received prior dosing; these tissues had covalent binding indices of 14.2, 4.3, and 3.7 µmol/mol nucleotides/dose, respectively. Protein and RNA were the major macromolecular targets for binding of radioactivity from [¹⁴C]aniline. Relative to controls, most tissues from predosed mice (low dose and high dose) showed less binding to protein and RNA; but for most tissues from predosed rats administered 50-mg/kg doses of [¹⁴C]aniline, there was more extensive binding. Also relative to controls, binding of radioactivity in the spleen of predosed rats given [¹⁴C]aniline (50 mg/kg) was 148% greater for protein and 302% greater for RNA. For rate administered 250 mg of [¹⁴C]aniline per kg, however, there were no outstanding differences in binding to RNA and protein between normal and predosed animals.

The profiles of urinary metabolites produced by rats and mice were not appreciably different in animals predosed with aniline. For rats, however, the profiles were different for the low and high doses, suggesting that the main metabolic pathway was saturated at the higher dose. p-Acetamidophenyl sulfate represented over 70% of the total radioactivity recovered from the urine of rats dosed with 50 mg of aniline per kg but only 30% in the urine of those dosed with 250 mg/kg. The urine of the high-dose rats contained greater percentages of p-aminophenyl sulfate, p-acetamidophenyl glucuronide, and unconjugated metabolites. In mouse urine, p-acetamidophenyl glucuronide, representing 29 to 32% of the total radioactivity, was the major metabolite. Nevertheless, mice produced more ortho derivatives than did rats, for in acid-treated urine, the ratio of p- to o-aminophenol was 8.1 for rats and 1.6 for mice.

Predosing of rats and mice did not change the kinetic values for liver aniline p-hydroxylase or N-hydroxylase but increased the amount of mouse liver cytochrome P-450 from 0.231 to 0.491 nmol/mg protein. For p-hydroxylase of rat liver, the apparent K_m value was higher, and the apparent V_max value lower than in mouse liver. Kinetic values for rat and mouse N-hydroxylase were similar.

These results suggest that the difference in carcinogenic susceptibility of these two species to aniline is due to differences in metabolism of this compound, with high doses to rats leading to the production of larger quantities of reactive metabolites.

¹ This work was supported by Grant 1RO1-CA30296, National Cancer Institute, NIH, Department of Health and Human Services.

² To whom requests for reprints should be addressed.

Received 8/ 8/83. Accepted 9/26/84.

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