Cisplatin induces renal expression of P-glycoprotein and canalicular multispecific organic anion transporter.
The expression of two members of the ATP-binding cassette family of transport proteins, P-glycoprotein (P-gp) and the canalicular multispecific organic anion transporter (cMOAT or Mrp2), was evaluated in renal brush-border membranes (BBM) and various rat tissues after cisplatin treatment. One administration of cisplatin (5 mg/kg) increased P-gp expression by >200-300% in renal BBM and in crude membranes from liver and intestine. The increase in P-gp expression in the kidney was also detected in photolabeling experiments, suggesting the induction of functional P-gp. cMOAT expression was increased by >10-fold in renal BBM after cisplatin administration, although it had no effect on liver cMOAT expression. The increase in the levels of both proteins was maximal at 2 days after cisplatin treatment and lasted for at least 8 days. These results indicate that a single administration of cisplatin induces overexpression of P-gp and cMOAT in specific tissues. This may be of significant relevance to the design of clinical trials using cisplatin as a single chemotherapeutic agent or in combination with other drugs.
Demeule
M
M
Laboratoire de Médecine Moléculaire, Département de Chimie-Biochimie, Université du Québec à Montréal, Montreal, Quebec H3C 3P8, Canada.
Brossard
M
M
Béliveau
R
R
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000818:Animals; D027321:Anion Transport Proteins; D001921:Brain / Q000378:metabolism; D002196:Capillaries / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics*; D002462:Cell Membrane / Q000378:metabolism; D002560:Cerebrovascular Circulation; D002945:Cisplatin / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D008871:Microvilli / Q000378:metabolism; D009928:Organ Specificity; D051381:Rats; D017207:Rats, Sprague-Dawley
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D027321:Anion Transport Proteins; D002352:Carrier Proteins; D002945:Cisplatin