Date of Award

1986

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Abstract

This study was designed to investigate the hepatotoxicity and urinary metabolites of 2,4- and 2,6-DMA in the dog and rat and the covalent binding of the two isomers in the rat as differences in metabolism may be related to the divergent hepatic responses. Male Beagles were orally dosed for 1 or 10 days with 2,6- or 2,4-DMA at 25 mg/kg. Male Fischer 344 rats were gavaged with 2,6- or 2,4-DMA at 25% of their respective LD50's (262.5 mg/kg; 117/mg/kg) for the same time period. The effects of phenobarbital (PB), 3-methylcholanthrene (3MC) and SKF-525A on the hepatotoxicity and metabolites of 2,4- and 2,6-DMA were also investigated. 24 Hr. urine samples were analysed by GC and GC/MS; liver sections were evaluated by light and electron microscopy. A final group of rats received ('14)C-2,4- or -2,6-DMA after a 9 day pretreatment with nonlabelled compounds. 2,6-DMA induced hepatic fatty degeneration in all treated dogs; 2,4-DMA caused no detectable lesions. In rats 2,6-DMA produced no significant liver lesions, whereas 2,4-DMA induced hepatomegaly and a subtle but distinct change characterized by swollen cells with voluminous homogeneous cytoplasm and segregation or clumping of cytoplasmic substructures. Concurrent treatment with PB and 2,4-DMA resulted in death of 50% of the animals by Day 5. 3MC treatment enhanced the 2,4-DMA lesion. 2,4-DMA alleviated an SKF-525A - induced midzonal fatty degeneration of the liver, whereas 2,6-DMA was less effective in this regard. The major urinary metabolite of 2,4-DMA in the dog was 6-hydroxy-2,4-DMA. Minor metabolites included 4-amino-3-methyl-benzoic acid and N,2,4-trimethylaniline. The major urinary metabolite of 2,6-DMA was 4-hydroxy-2,6-DMA. Minor metabolites included 2-amino-3-methyl-benzoic acid, N,2,6-trimethylaniline, 2,6-dimethylnitrosobenzene, 4-imino-3,5-dimethyl-quinone, and the glycine conjugate of the benzoic acid. Rats produced N-acetyl-4-amino-3-methyl-benzoic acid as the major metabolite of 2,4-DMA and N,2,4-trimethylaniline in small amounts. 2,6-DMA was primarily excreted as 4-hydroxy-2,6-DMA; N,2,6-trimethylaniline was a minor metabolite. The covalent binding of ('14)C-2,4-DMA to rat hepatic DNA, RNA or protein was significantly greater than that of ('14)C-2,6-DMA. The above results appear to indicate that differences in metabolism, with possible activation to reactive metabolite(s), are important in the divergent hepatic effects of 2,4- and 2,6-DMA in the rat and dog. (Abstract shortened with permission of author.).

Pages

220

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