Peter B. Smith
Exposure of living organisms to foreign chemicals (xenobiotics) often leads to physiologic disturbances culminating in cytotoxicity, mutation and cell transformation. The disturbance is frequently initiated when the xenobiotic is converted into reactive metabolites by enzyme systems native to the target cell. The cytochromes P-450 and flavin-dependent monooxygenase (FMO) consist of a family of isozymes which catalyze these conversions. Both families are found in most mammalian tissues and exist in individual cells as a mixture of isozyme types. The objective of my work is to construct mammalian cell lines with a defined metabolic phenotype for individual P-450 and FMO isozymes. Flavin monooxygenase is of particular interest because these isozymes exhibit a broad substrate specificity for activating hydrazine, thiocarbamide, and thioamide classes which are common reactive groups in therapeutic drugs. Additionally, FMO is a major contributor to the metabolism of agrichemicals and may be responsible for producing metabolites toxic to mammalian cells. In the laboratory, retroviral vectors are used to fix the cDNA for hepatic and pulmonary forms of P-450 and FMO into the genome of various mammalian cell lines. These cells now express a new metabolic capability for activating those xenobiotics that are substrates for the P-450 or FMO originally chosen by the investigator. Such cell lines offer an in vitro approach for exploring the biochemical basis of selective toxicity.
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