Diallyl disulfide, a chemopreventive agent in garlic, induces multidrug resistance-associated protein 2 expression.
The organosulfur compounds (OSCs), present in garlic, are studied for their protective effect against human cancers. P-glycoprotein (P-gp) and multidrug resistance protein 2 (Mrp2) are two transporters involved in the defense of cells and in the development of multidrug resistance. Whereas OSCs increase glutathione S-transferase activity (GST), Mrp2 plays a role in the transport of glutathione (GSH)-conjugates. In this study, we have investigated the effect of two OSCs, diallyl disulfide (DADS) and S-allyl cysteine (SAC), on P-gp and Mrp2 expression in renal brush-border membranes. By Western blot analysis, our results show that DADS induces Mrp2 expression (by 7-fold), which correlates with the rise of GST activity and GSH levels. Surprisingly, a co-administration of OSC with cisplatin, an anticancer drug, significantly increased Mrp2 gene and protein expression (by 30-fold), suggesting that DADS could potentiate the effects of cisplatin. Interestingly, SAC and cisplatin in co-treatment decreased P-gp protein expression and mdr1b isoform mRNA levels. In addition, modulation of the mdr1b isoform and Mrp2 by cisplatin was completely abolished by a glutathione precursor, N-acetyl cysteine. These results indicate that OSCs present in a garlic-rich diet might alter chemotherapeutic treatments using P-gp or Mrp2 substrates.
Laboratoire de Médecine Moléculaire, Hôpital Sainte-Justine, Université du Québec à Montréal, Succursale centre-ville, CP 8888, Montréal, Qué., Canada H3C 3P8.
Michel
M
Demeule
Mathieu
M
Brossard
Sandra
S
Turcotte
Anthony
A
Regina
Julie
J
Jodoin
Richard
R
Béliveau
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000111:Acetylcysteine / Q000378:metabolism; D000498:Allyl Compounds / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology; D003545:Cysteine / Q000031:analogs & derivatives* / Q000378:metabolism; D004220:Disulfides / Q000378:metabolism / Q000494:pharmacology*; D005737:Garlic / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D007672:Kidney Cortex / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008871:Microvilli / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000096:biosynthesis* / Q000235:genetics; D010936:Plant Extracts / Q000494:pharmacology*; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012269:Ribosomal Proteins / Q000096:biosynthesis* / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000096:biosynthesis* / Q000235:genetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000498:Allyl Compounds; D016588:Anticarcinogenic Agents; D004220:Disulfides; C093947:MRP2 protein, S cerevisiae; D024101:Mitochondrial Proteins; D010936:Plant Extracts; D020033:Protein Isoforms; D012333:RNA, Messenger; D012269:Ribosomal Proteins; D029701:Saccharomyces cerevisiae Proteins; C028009:diallyl disulfide; C065299:S-allylcysteine; D005982:Glutathione Transferase; D005978:Glutathione; D003545:Cysteine; D002945:Cisplatin; D000111:Acetylcysteine