The xylidine 2,4-dimethylaniline (2,4-DMA) produces hepatic cholangiofibrosis, bile duct proliferation, and foci of cellular hyperplasia and degeneration in the rat. The same compound is relatively innocuous in the dog. 2,6-Dimethylaniline (2,6-DMA) does not produce hepatic lesions in the rat, except at high doses but is a potent inducer of fatty degeneration in the dog. The purpose of the present study was to examine pathways of in vivo metabolism of both isomers in the rat and dog. The major urinary metabolite of 2,4-DMA in the rat was N-acetyl-4-amino-3-methylbenzoic acid (AAMBA) while in the dog it was 6-hydroxy-2,4-dimethylaniline (6-HDMA). The dog also produced a smaller amount of unacetylated 4-amino-3-methylbenzoic acid (4-AMBA) and its glycine conjugate. 2,6-DMA was metabolized principally to 4-hydroxy-2,6-dimethylaniline (4-HDMA) in both species, but the dog also produced significant quantities of 2-amino-3-methylbenzoic acid (2-AMBA), along with trace amounts of the glycine conjugate of the latter and 2,6-dimethylnitrosobenzene. Trace levels of an unknown postulated to be 3,5-dimethyl-4-imino-quinone were also found in urine of dogs. In rats, repeated administration of either xylidine for 10 days failed to increase the appearance of metabolites, but 3-methylcholanthrene (3-MC) did increase the urinary concentration of AAMBA in 2,4-DMA dosed rats. The divergent pathways of metabolism in the 2 species could be responsible for species specific pathologies produced by these 2 xylidines. © 1989.
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