6533b835fe1ef96bd129e985

RESEARCH PRODUCT

Use of Mechanistic Information for Adequate Metabolic Design of Genotoxicity Studies and Toxicological Interactions of Drugs and Environmental Chemicals

subject

description

Microorganisms as well as mammalian cells used for mutagenicity investigations have little or no activities for metabolism of premutagens and precarcinogens, i.e. of compounds ultimately leading to mutations and cancer but first requiring metabolic activation. Therefore, to such cells an exogenous activating system is added, generally the postmitochondrial supernatant fraction of the liver homogenate and a NADPH-generating system (Ames et al. 1976). In this situation enzymes requiring cofactors other than NADP(H) are unlikely to be active. Thus, this metabolic system is rather artificial. Monooxygenases are active in this system. They, for example, convert polycyclic aromatic hydrocarbons to epoxides. These epoxides may be substrates for epoxide hydrolase, an enzyme which is also active in the test system because it requires no cofactor. The resulting diols may be further metabolized by monooxygenases to diol epoxides that are potent mutagens and carcinogens (Conney 1982). On the other hand, enzymes for conjugation reactions by which precursors of the ultimate mutagens could be sequestered are inactive, due to the low concentrations of their cofactors.