Synthetic and natural opiates interact with P-glycoprotein in multidrug-resistant cells.
The ability of P-glycoprotein (P-gp) to transport naturally occurring and synthetic opiate analgesics was investigated. Multidrug-resistant Chinese hamster ovary cells (B30) were found to accumulate significantly lower amounts of morphine than their drug-sensitive counterparts (B1). This decreased accumulation was reversed upon depletion of cellular stores of ATP. In addition, morphine bound to plasma membranes from B30 cells in a specific, saturable fashion. Verapamil and vinblastine, compounds transported by P-gp, were able to increase accumulation and displace the binding of morphine in B30 cells. In turn, the synthetic opiates meperidine, pentazocine, and methadone were able to increase the accumulation of vinblastine in resistant cells. These compounds were also able to displace the specific binding of vinblastine and the photoaffinity labeling of P-gp in plasma membranes by the radioiodinated anthracycline, iodomycin. The implications of these findings in relation to the distribution, tolerance, and gastrointestinal side effects of opiates are discussed.
Callaghan
R
R
Departments of Biochemistry and Clinical Biochemistry, University of Toronto, Ontario, Canada.
Riordan
J R
JR
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D016466:CHO Cells; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D003630:Daunorubicin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D004351:Drug Resistance; D007457:Iodine Radioisotopes; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000378:metabolism*; D009294:Narcotics / Q000378:metabolism*; D014700:Verapamil / Q000494:pharmacology; D014747:Vinblastine / Q000378:metabolism / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D007457:Iodine Radioisotopes; D008562:Membrane Glycoproteins; D009294:Narcotics; C060588:iodomycin; D014747:Vinblastine; D014700:Verapamil; D003630:Daunorubicin