Coordinated regulation of P-glycoprotein activity and cytochrome P-4501A induction in sublines of rat hepatoma McA RH7777 cells with different levels of colchicine resistance.
The constitutive and induced activities of cytochrome P-4501A isoforms in hepatoma McA 7777 sublines with different levels of colchicine (CH) resistance were studied. The higher CH resistance was associated with the elevated functional activity of P-glycoprotein (Pgp). The constitutive level of benzo(a)pyrene hydroxylase and 7-ethoxyresorufin O-deethylase (cytochrome P-4501A-dependent activities) were the same in sublines with different CH resistance levels. However, benzo(a)-anthracene, a cytochrome P-4501A inducing agent, more effectively induced benzo(a)pyrene hydroxylase and 7-ethoxyresorufin O-deethylase activities in sublines with elevated P-glycoprotein activity. The toxicity of benzo(a)pyrene, a compound which is simultaneously a cytochrome P-4501A-inducing agent and a toxic agent activated by cytochrome P-4501A, is more effective in sublines with elevated CH resistance. These results support the suggestion about the coordinated regulation of enzyme systems involved in the defence against various lipophilic xenobiotics. The possibility to overcome the Pgp-mediated MDR of some tumours by using a combination of some drugs including compounds which induce the cytochrome P-4501A isoforms and are activated by them is discussed.
Gujaeva
E L
EL
Institute of Carcinogenesis, Blochin Cancer Research Centre, Russian Academy of Medical Sciences, Moscow.
Kobliakov
V A
VA
Zabotina
T N
TN
Rybalkina
E J
EJ
Stravrovskaya
A A
AA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001580:Benzopyrenes / Q000494:pharmacology; D003078:Colchicine / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D008114:Liver Neoplasms, Experimental / Q000378:metabolism*; D010078:Oxazines / Q000494:pharmacology; D051381:Rats; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001580:Benzopyrenes; D010078:Oxazines; C014180:resorufin; D003577:Cytochrome P-450 Enzyme System; D014700:Verapamil; D003078:Colchicine