MULTIDRUG RESISTANCE AND MUTAGENESIS

Multidrug resistance, the phenomenon whereby the development of resistance to one drug is sometimes accompanied by the simultaneous development of resistance to a variety of other, often structurally unrelated, drugs, is frequently associated with the presence of an energy-dependent membrane-transport system which reduces the concentration of a drug or other chemical in the cytoplasm. The latter process (termed here MDR) occurs naturally in a number of normal mammalian tissues, including colon, jejunum, liver, kidney and bone marrow, as well as in other species including bacteria. The presence of MDR can reduce the mutagenic potential of a variety of compounds in mammalian and microbiological assays. MDR can be reversed by a diverse collection of compounds, many of which are hydrophobic cations with other physiological effects. An important consequence of these considerations is that MDR-reversing agents are potentially dangerous because, while having no intrinsic mutagenicity, they may significantly increase the mutagenicity of other compounds by poisoning protective MDR mechanisms in the body.