Multidrug resistance during chemical carcinogenesis: a mechanism revealed?

The classic Solt-Farber model of chemical carcinogenesis in rat liver (7) involves sequential treatment of rats with diethylnitrosamine, partial hepatectomy, and 2(acetylamino)fluorene (AAF). After several weeks, the rats develop multiple preneoplastic hepatic nodules, and some of these become frank hepatocarcinomas after several months. Cells derived from the nodules appear to be resistant to a variety of toxic agents (2). In humans, this may translate into the well-known intrinsic multidrug resistance of hepatocarcinomas. In this issue of the journal, Burt and Thorgeirsson show that treatment with certain chemical carcinogens increases RNA levels for at least two proteins involved in cellular handling of toxic materials: (a) the multidrug transporter P-glycoprotein, an energy-dependent efflux system for natural product cytotoxic drugs that is the product of the MDR-1 gene (also known as PGY1) (3); and (b) cytochrome P-450 isoform d, a component of the system that oxidizes potentially harmful xenobiotics (4). Does this coordinate increase in levels of RNA for two potential detoxifying systems account for the multidrug resistance of chemically induced tumors and perhaps other cancers as well, and does it reflect a global regulatory mechanism that controls expression of detoxifying systems?