Biomedical subjects
Publications and source records attributed to I R Rowland.
Most strains of staphylococci, streptococci, yeasts and E. coli isolated from human faeces, could synthesize methylmercury compounds. In contrast, few strains of obligate anaerobes could do so. Up to 6 ng methylmercury/ml were formed in 44 h from 2 mug mercuric chloride.
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A major proportion of bacterial types, common in the gastrointestinal tract of many animals and man, were active in degrading diphenylnitrosamine and dimethylnitrosamine, the former being degraded more rapidly than the latter. At low nitrosamine concentrations (is less than 0.05 micronmol/ml), approximately 55% of added diphenylnitrosamine, 30% of N-nitrosopyrrolidine, and 4% of dimethylnitrosamine were degraded. The route of nitrosamine metabolism by bacteria appears to be different from that proposed for breakdown by mammalian enzyme systems in that carbon dioxide and formate were not produced. In bacteria, the nitrosamines were converted to the parent amine and nitrite ion and, in addition, certain unidentified volatile metabolites were produced from dimethylnitrosamine by bacteria. The importance of bacteria in reducing the potential hazard to man of nitrosamines is discussed.
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To investigate the involvement of bacterial enzyme activities in the biotransformation of xenobiotic compounds, we have developed a simulation of the rat hindgut microflora in vitro. This mixed bacterial population exhibits many similarities to the native rat flora, and the diversity of bacterial species and the activity of a number of hydrolytic and reductive enzymes (e.g. azoreductase, beta-glucosidase, beta-glucuronidase, nitrate reductase and nitroreductase) are reproduced in the culture at levels similar to those found in the large intestine. The flora have been found to respond to an anutrient (cyclamate) or to host products (bile acids) with changes in enzyme activity, and to metabolize the azo dye Brown HT to metabolites qualitatively similar to those found in the faeces after oral administration to the rat. The experiments demonstrate that the bacterial population of the large intestine of the rat may be successfully cultured in vitro and provides and alternative to animal studies for the investigation of foreign compound metabolism by the flora.
Cultivation of E. coli B/r strain WP2 in low concentrations of either 4-nitroquinoline N-oxide (4NQO) or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) had no effect on the mutagenic or cytotoxic consequences of subsequent challenge with dichlorvos (DCV). However, although the sensitivity of E. coli cells taken from cultures grown in low concentrations of DCV to the effects of 4NQO was unchanged, the cells were more resistant to the mutagenic (but not cytotoxic) consequences of MNNG challenge. This phenomenon was not observed in WP2 derivatives deficient in either error-free (uvrA-) or error-prone (lexA-) DNA-repair, suggesting that a factor common to both these repair pathways may be involved.
The effect of intestinal flora on the absorption and dispositon of mercury in tissues was investigated using conventional rats, and rats treated with antibiotics to eliminate their gut flora. Antibiotic-treated rats given [203Hg]-labeled methylmercuric chloride orally had significantly more mercury in their tissues, especially in kidney, brain, lung, blood, and skeletal muscle, and also excreted less mercury in the feces than conventional rats. Furthermore, in the kidneys of the antibiotic-treated rats, the proportion of mercury present as organic mercury was greater than in the kidneys of the conventional rats. The results suppport the hypothesis that the metabolism of methylmercuric chloride by the gut flora reduces the tissue content of mercury. When rats were administered 10 mg methylmercuric chloride/kg . day for 6 days, four of five of those given antibiotics developed neurological symptoms of toxicity, whereas only one of five conventional rats given methylmercuric chloride was affected.
Mice fed either (1) a pelleted rodent diet, (2) evaporated milk, or (3) a synthetic diet (high protein, low fat) exhibited different rates of whole body mercury elimination and fecal mercury excretion after exposure (per os) to methylmercuric chloride. The percentage of the total mercury body burden present as mercuric mercury was highest (35.3%) in mice fed the synthetic diet (which had the highest rate of mercury elimination) and lowest (6.6%) in the animals having the lowest mercury elimination rate (milk-fed mice). Mice fed the synthetic diet had lower mercury concentrations and had a higher proportion of mercuric mercury in their tissues than the mice from the other dietary groups. Treatment of the mice with antibiotics throughout the experimental period to suppress the gut flora reduced fecal mercury excretion and the dietary differences in whole body retention of mercury. Tissue mercury concentrations and proportion of organic mercury in feces, cecal contents, liver, and kidneys were increased by antibiotic treatment of mice fed the pelleted or synthetic diets. These results are consistent with the theory that demethylation of methylmercury by intestinal microflora is a major factor determining the excretion rate of mercury.
The development of neurotoxicity in rats after exposure to methylmercuric chloride was monitored using behavioural indices. At selected time points the cellular localization of mercury and the relative amounts of organic and inorganic mercury were determined in several regions of the CNS, and in some non-neural tissues. The CNS showed an affinity for organic mercury, the levels of inorganic mercury remaining low throughout symptomatic intoxication. Histopathological changes were not closely related to the regional tissue content of the organic or inorganic forms, nor to mercury localized histochemically at the cellular level. The stained deposits, which had focal cytoplasmic distribution, appeared in glial cells initially then in larger neurones as the intoxication progressed. These observations may represent changes in the mercury content of different cell types or reflect differences in the way that they handle a similar burden of mercury. A transitory accumulation of mercury in glial cells may be a factor contributing to the occurrence of a latent period and sequestration of mercury in cytoplasmic organelles may serve to protect some cell types from injury.