Antimutagenesis Studies: Where Have They Been and Where Are They Heading?

抄録

An anti-mutagen is any substance that reduces the rate of spontaneous mutations or counteracts or reverses the action of a mutagen, or any technique that protects cells against the effects of mutagens. Studies as early as the 1940s reported on substances that delayed detection of radiation-induced mutations, or reduced the appearance of mutations induced by chemicals such as acridine orange. However, a far more sophisticated range of anti-mutagens is now being identified. Mutagen scavengers act through absorption onto a larger molecule that is readily excreted. Good examples are provided by dietary fibre sources, such as wheat bran, or the planar molecule, chlorophyll and its stabilised derivative, chlorophyllin. Mutagens may be actively extruded from human cells through the action of one or more of a series of ATP-binding cassette (ABC) drug transporter proteins, including the multidrug resistance proteins (P-glycoproteins), multidrug resistance-associated proteins (MRP1-7) and the breast cancer resistance protein (BCRP). These proteins can affect the absorption, distribution and excretion of mutagens and carcinogens, as well as of their metabolites and conjugates. Even if the undesirable compound enters the cells, there are several mechanisms by which it may be prevented from interaction with DNA. Detoxification mechanisms are of increasing interest, especially those where transcription is regulated through the antioxidant response element (ARE), whose own transcription factor, Nrf2, is repressed under basal conditions. While much of the early literature on mutagenesis and carcinogenesis implicated exogenous chemicals, it is increasingly realised that unrepaired oxidative DNA lesions are important mutational precursors, and anti-oxidants represent an important class of anti-mutagens. It is also recognised that deficiency of certain micronutrients may lead to cell mutation, and that restoring nutrient balance is an important mechanism of anti-mutagenesis. An increasing number of studies focus on DNA repair and stress responses as novel mechanisms of anti-mutagenesis.