Carcinogens, metabolic elimination

In mammals the cytochrome P-U50 mediated monooxygenase or mixed function oxidase system involved in the elimination of lipophilic environmental contaminants and other foreign compounds, has been implicated in the carcinogen activation process. There are several distinct variants of cytochrome P-U50 in mammalian tissues and there may be more than one form of this ubiquitous cytochrome also in fish. The significance of this lies in the fact that different forms of cytochrome P-U50 result in different metabolite patterns, which in turn may reflect on the carcinogenicity or toxicity of compounds being metabolized. 

Significant activation occurs during the microbial metabolism of trichloroethylene (TCE). This compound was once widely used and now represents a major contaminant of many aquifers. Because TCE is metabolized by many bacteria, its elimination by bioremediation is being actively pursued. However, a major product frequently encountered is vinyl chloride, a potent carcinogen ... 

In a carcinogenic study, male and female rats were given DMHP by gavage 5 days/week for 103 weeks. At 200mg/kg, there were increases in alveolar/bronchiolar carcinomas, squamous cell carcinomas of the lung, and carcinomas of the stomach in male rats. Neoplastic lesions did not occur in mice after similar treatments. Species-dependent differences in the metabolism of DMPH were limited to more rapid metabolism and elimination by mice compared with rats. Therefore, the... 

In mammalian liver microsomes, cytochrome P-450 is not specific and catalyzes a wide variety of oxidative transformations, such as (i) aliphatic C—H hydroxylation occurring at the most nucleophilic C—H bonds (tertiary > secondary > primary) (ii) aromatic hydroxylation at the most nucleophilic positions with a characteristic intramolecular migration and retention of substituents of the aromatic ring, called an NIH shift,74 which indicates the intermediate formation of arene oxides (iii) epoxidation of alkenes and (iv) dealkylation (O, N, S) or oxidation (N, S) of heteroatoms. In mammalian liver these processes are of considerable importance in the elimination of xenobiotics and the metabolism of drugs, and also in the transformation of innocuous molecules into toxic or carcinogenic substances.75 77... 

Ad 3) High dose selection based on saturation of absorption measured by systemic availability of drug-related substances is acceptable. The mid and low doses selected for the carcinogenicity study should take into account saturation of metabolic and elimination pathways. 

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