Multiple drug resistance, antimutagenesis and anticarcinogenesis

Many cells are protected from excess levels of exogenous chemicals, including mutagens and carcinogens as well as pharmaceutical agents, by being actively extruded through the action of one or more of a series of ATP-binding cassette drug transporter proteins. Those known to be important in humans are the multidrug resistance proteins (P-glycoproteins, encoded by the mdr 1 and 3 genes), multidrug-resistance-associated proteins (MRP1–7) and the breast cancer resistance protein (BCRP). These proteins have overlapping but distinct cellular locations and substrate specificities, and jointly govern the likelihood of penetration or distribution of a given mutagen or carcinogen into various tissues including the brain, testis, ovaries and fetus. Thus, they can affect the absorption, distribution and excretion of mutagens and carcinogens, as well as of their metabolites and conjugates, in most cases acting to prevent or reduce mutagenesis or carcinogenesis. However, because ABC transporters may limit the success of chemotherapy, there has been a considerable effort by the pharmaceutical industry to develop inhibitors of this transport process, and these are increasing in use. In general, the mutagenicity of many chemicals may be increased at the cellular levels by the action of these inhibitors, while the altered absorption characteristics favour greater uptake into the body. Thus, in many cases, such inhibitors may counter the antimutagenic and anticarcinogenic effect of the multidrug resistance mechanisms. There are exceptions, however. An increasing number of single nucleotide polymorphisms in multidrug resistance genes are being identified in humans, and may account for many of the significant differences in inter-individual susceptibility to exogenous and endogenous mutagenic and carcinogenic insults.