DISPOSITION AND METABOLISM OF ANILINE IN FISCHER 344 RATS AND C57BL/6 X C3H F1-MICE

  • 1 January 1985
    • journal article
    • research article
    • Vol. 45  (1) , 174-180
Abstract
The metabolism and disposition of aniline, which induces spleen hemangiosarcomas in rats but no tumors in mice, was examined in normal and predosed Fischer 344 rats, and C57BL/6 .times. 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 .mu.mol/mol nucleotides per 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 rats 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 29-32% 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 Km value was higher, and the apparent Vmax value lower than in mouse liver. Kinetic values for rat and mouse N-hydroxylase were similar. The difference in carcinogenic susceptibility of these 2 species to aniline evidently is due to differences in metabolism of this compound, with high doses to rats leading to the production of larger quantities of reactive metabolites.