Microsomal tumors

It appears that considerable metabolism of nitrosamines takes place in the liver, from the finding that most of them are activated by rat liver microsomes to bacterial mutagens. However, relatively few nitrosamines induce liver tumors in rats. The most common target is the esophagus and a wide variety of nitrosamines induce tumors in this organ of rats, some only tumors of the esophagus, others tumors of other organs also. 

Fabacher, D.L. and P.C. Baumann. 1985. Enlarged livers and hepatic microsomal mixed-function oxidase components in tumor-bearing brown bullheads from a chemically contaminated river. Environ. Toxicol. Chem. 4 703-710. 

The herbicide alachlor (4.146, Fig. 4.7) also displayed species-dependent toxicity, since it induced nasal tumors in rats but not in mice. Its metabolic scheme in rats and mice (Fig. 4.7) shows that alachlor can be transformed into 2,6-diethylaniline (4.149) by two different pathways, one of which proceeds via formation of 4.147. The other pathway implies glutathione (GSH) conjugation, followed by /3-lyase-mediated liberation of the thiol, followed by S-methylation to produce the methylsulfide 4.148. The two secondary amides 4.147 and 4.148 were hydrolyzed by microsomal arylamidases, but alachlor itself was not a substrate for this enzyme. The hydrolytic product 2,6-diethylaniline (4.149) was oxidized in nasal tissues to the electrophilic quinonimine metabolite 4.150, which can bind covalently to proteins. Aryl-... 

In mice, also, deacetylation is involved in the hepato-carcinogenesis induced by 2-(acetylamino)fluorene. Indeed, BNPP-inhibited DNA-adduct formation in murine liver microsomes as well as tumor initiation by A-hydroxy-2-(acetylamino)fluorene in infant male B6C3Fj mice [100],... 

C. C. Lai, E. C. Miller, A. Liem, The Essential Role of Microsomal Deacetylase Activity in the Metabolic Activation, DNA-(Deoxyguanosin-8-yl)-2-aminofluorene Adduct Formation and Initiation of Liver Tumors by A-Hydroxy-2-acetylaminofluorene in the Livers of Infant Male B6C3Fj Mice , Carcinogenesis 1988, 9, 1295-1302. 

RT-PCR often brain tumors reveals none positive for CYP3A4 (Knupfer et al., 1999). Phenobarbital induces CYP3A1 mRNA in rat striatum and cerebellum (Schilter et al., 2000). Rat and human brain microsomes demethylate amitriptyline. Chemical and antibody inhibition suggests CYP3A4 is responsible (Voirol et al., 2000). 

Toxicological studies have suggested that the species specificity for induction of ovarian tumors (produced in mice but not rats) occurs because the blood level of the ovotoxic VCH metabolite VCH-1,2-epoxide is dramatically higher in VCH-treated female mice compared with rats. VCH has been shown to be metabolized by the liver of mice to the ovotoxic metabolite (VCH-1,2-epoxide), which circulates in blood and is delivered to the ovary, where it destroys small oocytes. This destruction of small oocytes is considered to be an early event in carcinogenesis. Species difference in epoxidation of VCH by hepatic micro-somes correlates well with the differences observed in the blood concentration of VCH-1,2-epoxide and VCH ovarian toxicity. Further in vitro studies have found that the rate of VCH epoxidation in humans by human hepatic microsomes was 13- and 2-fold lower than epoxidation by mouse and rat systems respec-tively. Therefore, if the rate of hepatic VCH epoxidation is the main factor that determines the ovotoxicity of VCH, rats may be a more appropriate animal model for humans. 

It is clear that the effects of induction or inhibition of the metabolism will be complex because of the large number of possible metabolic pathways through which benzofalpyrene may be metabolized. For instance, the microsomal enzyme inducer 5,6-benzoflavone inhibits the carcinogenicity of benzofalpyrene in mouse lung and skin, whereas inhibitors such as SKF 525A may increase the tumor production from certain polycyclic hydrocarbons. 

Newaz, S.N., Fang, W.-F. Strobel, H.W. (1983) Metabolism of the carcinogen 1,2-dimethylhydrazine by isolated human colon microsomes and human colon tumor cells in culture. Cancer, 52, 794-798... 

Cyclophosphamide in its parent form does not have direct cytotoxic effects, and it must be activated to cytotoxic forms by microsomal enzymes (Figure 55-5). The liver microsomal cytochrome P450 mixed-function oxidase system converts cyclophosphamide to 4-hydroxycyclophosphamide, which is in equilibrium with aldophosphamide. These active metabolites are believed to be delivered by the bloodstream to both tumor and normal tissue, where nonenzymatic cleavage of aldophosphamide to the cytotoxic forms—phosphoramide mustard and acrolein—occurs. The liver appears to be protected through the enzymatic formation of the inactive metabolites 4-ketocyclophosphamide and carboxyphosphamide. 

Thus, it can be easily theorized that the shift seen in the microsomal enzyme and cytochrome patterns caused by dietary fat and antioxidants may be related to the inhibitory and enhancing effects of these compounds on chemical carcinogenesis. Further studies are indicated to look at specific carcinogen metabolites produced by the drug metabolizing systems of animals consuming the various diets, and to attempt to correlate the corresponding cytochrome and enzyme levels with these metabolites and ultimately with resultant tumor incidences and tumor numbers. 

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