title: Diallyl disulfide and diallyl trisulfide up-regulate the expression of the pi class of glutathione S-transferase via an AP-1-dependent pathway.
abstract: Garlic organosulfur compounds are recognized as potential chemopreventive compounds. This protection is related to the induction of phase II detoxification enzymes. We previously reported that diallyl disulfide (DADS) and diallyl trisulfide (DATS) up-regulate the gene expression of the pi class of glutathione S-transferase (GSTP) and that an enhancer element named GPE I is required for this induction. In the present study, we further investigated the signal pathway involved in DADS and DATS up-regulation of this detoxification enzyme in Clone 9 cells. Cells were cultured with 25-200 micromol/L of DADS or DATS for 24 h. Western and Northern blots showed that both garlic allyl sulfides concentration dependently induced GSTP protein and mRNA expression, respectively. Changes in GST activity toward ethacrynic acid were consistent with the increase in GSTP expression (P < 0.05). Electromobility gel shift assay showed that the DNA binding activity of nuclear activator protein-1 (AP-1) is concentration-dependently increased in the presence of DADS and DATS as compared with that of the control cells. The phosphorylation of c-Jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), but not of p38, was stimulated in the presence of both garlic allyl sulfides. Pretreatment with SP600125 and PD98059, which are JNK and ERK inhibitors, respectively, abolished the increase in AP-1-DNA binding activity and also the induction of GSTP protein by either allyl sulfide. Our results indicate that the effectiveness of DADS and DATS on GSTP expression is likely related to the JNK-AP-1 and ERK-AP-1 signaling pathways and, thus, that DADS and DATS enhance the binding of AP-1 to GPE I.
authors.affiliation: Department of Nutrition and School of Dentistry, Chung Shan Medical University, No. 110 Sec. 1 Chien-Kuo N. Road, Taichung 40203, Taiwan.
authors.forename: Chia-Wen
authors.initials: CW
authors.lastname: Tsai
authors.forename: Haw-Wen
authors.initials: HW
authors.lastname: Chen
authors.forename: Jaw-Ji
authors.initials: JJ
authors.lastname: Yang
authors.forename: Lee-Yan
authors.initials: LY
authors.lastname: Sheen
authors.forename: Chong-Kuei
authors.initials: CK
authors.lastname: Lii
mesh_terms: D000498:Allyl Compounds / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D004220:Disulfides / Q000494:pharmacology*; D005737:Garlic / Q000737:chemistry; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D051549:Glutathione S-Transferase pi / Q000235:genetics*; D008099:Liver; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D013440:Sulfides / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000498:Allyl Compounds; D004220:Disulfides; D012333:RNA, Messenger; D013440:Sulfides; D018808:Transcription Factor AP-1; C042577:diallyl trisulfide; C028009:diallyl disulfide; D051549:Glutathione S-Transferase pi