Cunninghamella elegans metabolized 1-and 2-methylnaphthalene primarily at the methyl group to form 1-and 2-hydroxymethylnaphthalene, respectively. Other compounds isolated and identified were 1-and 2naphthoic acids, 5-hydroxy-1-naphthoic acid, 5-hydroxy-2-naphthoic acid, 6-hydroxy-2-naphthoic acid, and phenolic derivatives of 1-and 2-methylnaphthalene. The metabolites were isolated by thin-layer and reverse-phase high-pressure liquid chromatography and characterized by the application of UV-visible absorption, 1H nuclear magnetic resonance, and mass spectral techniques. Experiments with [8-14C]2methylnaphthalene indicated that over a 72-h period, 9.8% of 2-methylnaphthalene was oxidized to metabolic products. The ratio of organic-soluble to water-soluble metabolites at 2 h was 92:8, and at 72 h it was 41:59. Enzymatic treatment of the 48-h aqueous phase with either ,-glucuronidase or arylsulfatase released 60% of the metabolites of 2-methylnaphthalene that were extractable with ethyl acetate. In both cases, the major conjugates released were 5-hydroxy-2-naphthoic acid and 6-hydroxy-2-naphthoic acid. The ratio of the water-soluble glucuronide conjugates to sulfate conjugates was 1:1. Incubation of C. elegans with 2-methylnaphthalene under an 1802 atmosphere and subsequent mass spectral analysis of 2hydroxymethylnaphthalene indicated that hydroxylation of the methyl group is catalyzed by a monooxygenase. Naphthalene and methylnaphthalenes are among the most toxic components in the water-soluble fraction of crude and fuel oils (1, 2, 12, 21). These compounds have also been identified in commercial mosquito repellants (22, 23) and in an aromatic. hydrocarbon solvent, Aerotex 3470 (18). There has been concern about the occurrence, transport, and environmental fate of naphthalene and methyl-substituted naphthalenes because they have been shown to accumulate in vertebrate and invertebrate freshwater and marine organisms (1, 13). The toxic effects of these compounds could be due to the naphthalene and its methyl-substituted derivatives or one or more of their biotransformation products or both. The mechanism of the toxicity of naphthalene and methylsubstituted naphthalenes has not been determined. The metabolism of 1-and 2-methylnaphthalene has been investigated in bacteria, cyanobacteria, rats, and rainbow
Dinitropyrenes (DNPs) are highly mutagenic in the Salmonella reversion assay and are tumorigenic in rodents. Bacterial nitroreductases have been implicated in the mutagenic activation of DNPs. In this study, we investigated the metabolism of 1,8‐dinitropyrene (1,8‐DNP) by anaerobic bacterial suspensions derived from human feces, and the intestinal contents of rhesus monkeys and rats. The 1,8‐DNP metabolites were isolated by reversed‐phase high performance liquid chromatography, and identified by comparison of their chromatographic and mass spectral properties with those of authentic compounds. All of the intestinal microflora metabolized 1,8‐DNP to 1‐amino‐8‐nitropyrene and 1,8‐diaminopyrene. The mutagenic activity of samples extracted from incubations of human or rat intestinal microflora cultured with 1,8‐DNP was measured by reversion of Salmonella typhimurium TA98. There was a decrease in the mutagenic activities of the extracts with time of incubation that correlated with increased 1‐amino‐8‐nitropyrene and 1,8‐diaminopyrene formation. The decreased mutagenicity of the 1,8‐DNP metabolites was confirmed by conducting assays with authentic 1‐amino‐8‐nitropyrene and 1,8‐diaminopyrene. Both compounds showed much lower mutagenic activity compared to 1,8‐DNP. The results indicate that intestinal microflora have the ability to metabolize 1,8‐DNP to amine derivatives that are less mutagenic than the parent compound.
1. Strains of the fungus Cunninghamella elegans ATCC 9245 and 36112 were tested for their ability to transform the antihistamines methapyrilene (I), thenyldiamine (II) and tripelennamine (III). 2. Antihistamine metabolites were isolated by h.p.l.c., and identified by their 1H-n.m.r. and mass spectral properties. 3. All three drugs were transformed by both C. elegans strains to N-oxidized and N-demethylated derivatives. Metabolism during 96 h of incubation amounted to 85% for (I), 64% for (II), and 83% for (III). Metabolites soluble in organic solvents amounted to 62% to 86% of the total metabolism; approximately 88% to 95% of the organic-soluble metabolites were N-oxide derivatives of each antihistamine.
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