Mutation Research, 285 (1993)79-90 79 © 1993ElsevierSciencePublishers B.V. All rights reserved0027-5107/93/$06.00 MUT 00041 Multidrug resistance and mutagenesis Lynnette R. Ferguson and Bruce C. Baguley Cancer Research Laboratory, Universityof Auckland School of Medicine, Auckland, New Zealand (Received 11 May 1992) (Accepted29 May 1992) Keywords: Multidrugresistance and mutagenesis; Membrane-transportsystem,energy-dependent; Mutagenicpotential Summary 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 mem- brane-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. Multidrug resistance is a term coined from cancer chemotherapy, and is based on the obser- vation that the development of resistance to one drug is sometimes associated with the simultane- ous development of resistance to a variety of other, often structurally unrelated, drugs (Beck, 1987; Endicott and Ling, 1989; Pastan and Gottesman, 1991). A classical example is pro- vided by the observation that tumour cells devel- oping resistance to the Vinca alkaloid vincristine Correspondence: Dr. L.R. Ferguson,Cancer Research Labo- ratory, University of Auckland Schoolof Medicine,Auckland, New Zealand. Tel. (64-9)3737999;Fax (64-9)3737502. simultaneously develop resistance to unrelated anticancer drugs such as actinomycin D, doxoru- bicin and etoposide (Biedler and Riehm, 1970; Dano, 1972). Several types of multidrug resis- tance have been described, but the best known type, termed here MDR, is associated with in- creased activity of an energy-dependent efflux system (Skovsgaard, 1978). Although originally described in tumour cells, MDR is now known to be present in a variety of cells and probably has a natural function related to detoxification. MDR, because it can act on a variety of mutagens, is important for the consideration of the target tis- sues for environmental mutagens and carcino- gens. Furthermore, since MDR can occur in bac-