Enzymes mixed-function oxidase, protective

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. 

We observed a protective effect of increased dietary protein on DMBA-induced breast tumor incidence when the diets varying in protein were fed prior to carcinogen administration. We have investigated the hypothesis that dietary protein may influence carcinogenesis via effects on the mixed-function oxidase (MFO) enzyme systems involved in carcinogen metabolism. 

The effects of pyrrolizidine alkaloids on the mixed-function oxidase enzyme system in rat liver have been studied.79,80 Dehydroheliotridine and heliotrine (at higher dose rates) have similar effects on pregnant rats and their embryos.81 The development of pulmonary hypertension and obstructive lesions in rats after administration of monocrotaline (48) has been studied.82 Butylated hydroxyanisole protects young mice against the acute toxicity of monocrotaline.83 Reduced levels of pyrrole metabolites were observed. 

Several pesticides and other xenobiotics are metabolized in plants by mixed-function oxidases which are cytochrome P-450-dependent [28]. Inhibitors of such enzymes might therefore serve as synergists of herbicides or other crop protection compounds which are oxidatively degraded. Therefore, it has been logical to test whether the growth retardants believed to be oxygenase inhibitors would interfere with xenobiotic metabolism. Under in vitro conditions it has indeed been observed that tetcyclacis at relatively low concentrations inhibits the metabolism of the herbicide chlortoluron [10]. Similarly, the herbicidal activity of bentazon could be enhanced by tetcyclacis which, most likely, reduced its oxidative inactivation [18]. Further studies will, however, be required to find out whether such effects can be used under practical conditions. 

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