COORDINATE REGULATION OF P-GLYCOPROTEIN ACTIVITY AND CYTOCHROME P-4501A INDUCTION IN SUBLINES OF RAT HEPATOMA MCA RH-7777 CELLS WITH DIFFERENT LEVELS OF COLCHICIN RESISTANCE

The constitutive and induced activities of cytochrome P-4501A isoforms in hepatoma MCA 7777 sublines with different levels of colchicin (CH) resistance were studied. The higher CH resistance was associated with the elevated functional activity of P-glycoprotein (P-gp). The consti tutive level of benzo(a)pyrene bydroxylase and 7-ethoxyresorufine deet hylase (cytochrome P-4501A-dependent activities) were the same in subl ines with different CH resistance levels. However benzo(a)anthracene a cytochrome P-4501A inducing agent, more effectively induced benzo(a)p yrene hydroxylase and 7-ethoxyresorufine deethylase activities in subl ines with the elevated P-glycoprotein activity. The toxicity of benzo( a)pyrene, a compound which is at the same time a cytochrome P-4501A-in ducing agent and a toxic agent activated by cytochrome P-4501A, is mor e effective in sublines with the elevated CH resistance. The results c onfirm the suggestion about the coordinate regulation of enzyme system s involved in the defence against various lipophilic xenobiotics. The possibility to overcome the P-gp-mediated MDR of some tumours by using a combination of some drugs including compounds that induce the cytoc hrome P-4501A isoforms and are activated by them is discussed.