Metabolism dimethylnitrosamine

Diaz Gomez MI, Godoy HM, Castro JA. 1981. Further studies on dimethylnitrosamine metabolism, activation and its ability to cause liver injury. Arch Toxicol 47 159-168. 

Johansson EB, Tjalve H. 1978. The distribution of (14C)dimethylnitrosamine in mice. Autoradiographic studies in mice with inhibited and noninhibited dimethylnitrosamine metabolism and a comparison with the distribution of (14C)formaldehyde. Toxicol Appl Pharmacol 45 565-575. 

Garro, A. J., Seitz, H. K., and Lieber, C. S., 1981, Enhancement of dimethylnitrosamine metabolism and activation to a mutagen following chronic ethanol consumption. Cancer Res. 41 120. 

The above scheme satisfies much of the metabolic data however, some of it is speculative, and it is certainly incomplete. The evidence for the formation of the a-hydroxylated intermediate is circumstantial. The acetate ester of a-hydroxylated dimethylnitrosamine has been prepared (12.13) and has been found to be a potent, directly acting carcinogen (14). Other esters of a variety of a-hydroxylated nitros-amines have also been prepared (15). While it has been shown that DMN acetate is hydrolyzed to hydroxymethylmethyl-nitrosamine by an esterase enzyme, it has been pointed out that these derivatives of the a-hydroxylated nitrosamines also dissociate to N-nitrosoimmonium ions (15 16). 

The metabolic activity of various tissues is also a determinant of susceptibility to tumor production. The gastrointestinal tract is resistant to dime thy Ini trosamine carcinogenesis, even when the compound is given orally, as the metabolic activity of this organ is low as far as activation of dimethylnitrosamine is concerned. 

Dimethylnitrosamine is both a hepatic carcinogen and a hepatotoxicant. Does either effect require metabolism, and if so, what is (are) the metabolite(s) responsible for the carcinogenicity ... 

Haggerty HG, Holsapple MP. Role of metabolism in dimethylnitrosamine-induced immunosuppression a review. Toxicology 1990 63 1. 

Metabolism is required for both the carcinogenicity and direct cytotoxicity of dimethylnitrosamine. The metabolism of dimethylnitrosamine produces methyl diazonium ion which can fragment into a methyl carbonium ion which is believed to be the ultimate carcinogen and responsible for the liver necrosis. 

Alcohol plays an important role in the metabolism of foreign substances and is responsible for numerous interactions with drugs. A special type of cytochrome P 450 (P 450 II E 1) is induced by the chronic intake of alcohol. This subtype may influence other drug-metabolizing enzyme systems and possibly account for the carcinogenicity of dimethylnitrosamine in the gastrointestinal tract. 

A number of chemicals with demonstrable suppression of immune function produce this action via indirect effects. By and large, the approach that has been most frequently used to support an indirect mechanism of action is to show immune suppression after in vivo exposure but no immune suppression after in vitro exposure to relevant concentrations. One of the most often cited mechanisms for an indirect action is centered around the limited metabolic capabilities of immunocompetent cells and tissues. A number of chemicals have caused immune suppression when administered to animals but were essentially devoid of any potency when added directly to suspensions of lymphocytes and macrophages. Many of these chemicals are capable of being metabolized to reactive metabolites, including dime-thylnitrosamine, aflatoxin Bi, and carbon tetrachloride. Interestingly, a similar profile of activity (i.e., suppression after in vivo exposure but no activity after in vitro exposure) has been demonstrated with the potent immunosuppressive drug cyclophosphamide. With the exception of the PAHs, few chemicals have been demonstrated to be metabolized when added directly to immunocompetent cells in culture. A primary role for a reactive intermediate in the immune suppression by dimethylnitrosamine, aflatoxin Bi, carbon tetrachloride, and cyclophosphamide has been confirmed in studies in which these xenobiotics were incubated with suspensions of immunocompetent cells in the presence of metabolic activation systems (MASs). Examples of MASs include primary hepatocytes, liver microsomes, and liver homogenates. In most cases, confirmation of a primary role for a reactive metabolite has been provided by in vivo studies in which the metabolic capability was either enhanced or suppressed by the administration of an enzyme inducer or a metabolic inhibitor, respectively. 

In a comparison of the metabolic activation of dimethylnitrosamine by liver, lung, and kidney microsomes from male and female C57BL/6J mice, the existence of a sex difference in DMNA activation with kidney microsomes was demonstrated in that the female mice could not metabolize DMNA to a mutagen. 71 Similar sex differences were not observed in studies with Sprague-Dawley or Fischer rats. 

Crygan P, Greim H, Garro AJ, et al. 1973. Microsomal metabolism of dimethylnitrosamine and the cytochrome P-450 dependency of its activation to a mutagen. Cancer Res 33 2983-2986. 

Dashman T, Kamm JJ. 1979. Effects of high doses of vitamin E on dimethylnitrosamine hepatotoxicity and drug metabolism in the rat. Biochem Pharmacol 28 1485-1490. 

Daugherty JP, Clapp NK. 1976. Studies on nitrosamine metabolism I. Subcellular distribution of radioactivity in tumor-susceptible tissues of RFM mice following administration of (14C)dimethylnitrosamine. Life Sciences 19 265-271. 

Diaz Gomez MI, Swann PF, Magee PN. 1977. The absorption and metabolism in rats of small oral doses of dimethylnitrosamine. Biochem J 164 497-500. 

Hadjiolov D, Mundt D. 1974. Effect of aminoacetonitrile on the metabolism of dimethylnitrosamine and methylation of RNA during liver carcinogenesis. J Natl Cancer Inst 52 753-756. 

Magee PN. 1956. Toxic liver injury The metabolism of dimethylnitrosamine. Biochem J 64 676-682. 

Montesano R, Bresil H, Pegg AE. 1982. Metabolism of dimethylnitrosamine and repair of 0-6-methylguanine in DNA by human liver. In Magee PN, ed. Banbury report, Vol. 12, Nitrosamines and human cancer. Cold Spring Harbor, NY Cold Spring Harbor Laboratory, 141-152. 

Pegg AE, Perry W. 1981. Alkylation of nucleic acids and metabolism of small doses of dimethylnitrosamine in the rat. Cancer Res 41 3128-3132. 

Sirianni SR, Huang CC. 1987. Comparison of S9 fractions from rats, mice, and Chinese hamsters to metabolize dimethylnitrosamine and diethylnitrosamine to intermediates that induce sister-chromatid exchanges in V79 cells. Mutat Res 188 7-11. 

Swarm PF, Coe AM, Mace R. 1984. Ethanol and dimethylnitrosamine and diethylnitrosamine metabolism and disposition in the rat. Possible relevance to the influence of ethanol on human cancer incidence. Carcinogenesis 5 1337-1343. 

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