Parent carcinogen

At first three K-region oxides were studied, those of DMBA (XI), BP (XII) and phenanthrene, the non-carcinogenic parent (XIII) the structures are shown in Figure 8. These epoxides, which were considered very reactive, were found to remain stable both in air and in the X-ray beam when in the crystalline state (82, 83). 

Wang, Y.P., J. Yan, P.P. Fu, and M.W. Chou. 2005. Human Uver microsomal reduchon of pyrrolizidine alkaloid N-oxides to form the corresponding carcinogenic parent alkaloid. Toxicol. Lett. 155(3) 411-420. 

Although ultra accelerators or sulfur donors can be used together with primary accelerator (such as sulfenamide, TBBS) to improve cure rate as well as the heat resistance [16-18], their use is restricted because of the associated nitrosamine issue [19]. Accelerators derived from secondary amines, for example, MBS, TMTD, TETD, TMTM, and OTOS fall into this category. The combination of sulfenamide, such as CBS or TBBS, and a thiuram, such as TMTD or TETD, shows high-cure rates but suffers from the adverse effects on scorch resistance and vulcanizate dynamic property [20]. Additionally as previously mentioned, the use of TMTD or Tetraethylthiuram disulhde (TETD) or A-oxidiethylene dithiocarbamyl-A -oxidiethylene sulfenamide (OTOS) or 4,4 -Dithiodimorpholine (DTDM) is undesirable [21] due to concerns over carcinogenic nature of the A-nitrosamines formed from the parent amines. The solution to this originated by introduction of nitrosamine safe ultra accelerator such as TBzTD [22,23]. 

We have developed a quantitative structure-activity model for the variations in potency among the nitrosamines and, more recently, a related model for the variation in target organ for a smaller set of nitrosamines. We are currently developing a model for interspecies variation in susceptibility toward carcinogenic nitrosamines. The model for organ selectivity requires terms for the parent nitrosamine as well as for the hypothesized metabolites while the model for potency variations contains terms only for the unmetabolized parent compound. 

If, for example, the route from parent carcinogen to the actual biologically-active metabolite is considered as a multi-step pathway, the terms that appear in the model equation can be thought of as representing the rate-determining steps. 

The Ames test involves the reversion from a his— to his+ phenotype in any one of multiple bacterial strains (usually five strains are tested simultaneously). If the addition of test compound to a his— strain of bacteria allows them to grow on histidine deficient media, the obvious conclusion is compound-induced mutagenesis and a high potential hazard for the compound being carcinogenic. This test can also be conducted in the presence or absence of metabolic activation, in order to provide more information on potential risks (i.e., the parent compound may not be mutagenic, but the primary metabolite may present a safety risk). In practice, a positive Ames test almost always leads to discontinuing work on a compound of interest, and so these data are always collected prior to nomination of a compound for development. 

The developments which led to the present day concepts of the metabolic activation of hydrocarbons did not arise from the classical approach of identifying metabolites of greater biological potency than the parent compound, but from an approach dependent upon the assumption (or presumption) that the interaction of carcinogens with DNA is a key event in the initiation of the carcinogenic process. Brookes and Lawley (49) found in 1964 that when radioactive hydrocarbons are applied to the skin of mice, they become covalently bound to the DNA of the skin. Moreover, the extents of binding to DNA for various hydrocarbons followed fairly closely their relative carcinogenic activities. 

Benz[alanthracenes. The parent hydrocarbon is a weak carcinogen and the extent of modification of DNA in most in vivo systems is low. 

Parent, R.A., H.E. Caravello, and J.E. Long. 1992. Two-year toxicity and carcinogenicity study of acrolein in rats. Jour. Appl. Toxicol. 12 131-139. 

In an attempt to understand further the carcinogenicity of azathioprine, recent work in the authors laboratory has concentrated on the photodegradation of two compounds associated with the drug. l-Methyl-4-nitro-5-thioimid-azole is a metabolite and 5-hydroxy- l-methyl-4-nitroimidazole a hydrolysis product. Both gave, on irradiation at wavelengths greater than 300 nm, 1-methylparabanic acid (248) [152], The primary metabolites of azathioprine had previously been shown to be more potent than the parent drug as photosensitizers. Both 6-mercaptopurine and these imidazoles may play roles in its neoplastic action [151]. 

Exposure of various invertebrate species to high concentrations of petroleum did not induce mixed function oxidase activity. Enzyme activity was stimulated, however, in a number of fish tissues by petroleum. Different permutations can be addressed as to the significance of basal or induced levels of mixed function oxidases and hydrocarbon toxicity. AHH may have a physiological role in enhancing hydrocarbon clearance but may also increase the mutagenic-carcinogenic potential of hydrocarbons. Both of these concepts have been demonstrated in studies with fish (29,30). Induced AHH levels may permit a more rapid oxidative transformation with concomitant "disappearance" of parent hydrocarbons, but potentially toxic metabolites could be retained in tissues for longer periods (31). It is likely that at the enzymic level the... 

Letterman RD (ed) (1999) Water quality and treatment A handbook of community water supplies, 5th ed., Amer. Water Works Assoc., McGraw-Hill, New York Lijinsky W, Epstein SS (1970) Nitrosamines as environmental carcinogens. Nature 225 21-23 Lin S, Marshall EG, Davidson GK (1994) Potential parental exposure to pesticides and hmb reduction defects. Scand J Work Environ Health 20 166-179 Linak, E, Lutz, HJ, Nakamura E (1990) Chlorinated Solvents. In Linak E, Lutz HJ, Nakamura E, C2 chlorinated solvents, chemical economics handbook, Stanford Research Institute, Menlo Park, CA, pp. 632.30000a-632.3001z Lindsay WL (1979) Chemical equilibria in soils. John Wiley, New York... 

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