Diallyl sulfide induces heme oxygenase-1 through MAPK pathway.
Diallyl sulfide (DAS), is protective against chemically induced heptotoxicity, mutagenesis, and carcinogenesis. The mechanism of its protective effects is not fully understood. In this study, we found that DAS can induce the expression of heme oxygenase-1 (HO-1), which plays a critical role in the cell defense system against oxidative stress. DAS causes a dose- and time-dependent increase of HO-1 protein and mRNA level without toxicity in HepG2 cells. DAS-induced HO-1 protein expression is dependent on newly synthesized mRNA and newly synthesized protein. DAS increases Nrf2 protein expression, nuclear translocation, and DNA-binding activity. The MAP kinase ERK is activated by DAS. Both ERK and p38 pathways play an important role in DAS-induced Nrf2 nuclear translocation and ho-1 gene activation. DAS stimulates a transient increase of reactive oxygen species (ROS). N-Acetyl-cysteine blocked this increase of ROS production as well as DAS-induced ERK activation, Nrf2 protein expression and nuclear translocation, and ho-1 gene activation. The increase in HO-1 produced by DAS protected the HepG2 cells against toxicity by hydrogen peroxide or arachidonic acid. These results suggest that DAS induces ho-1 through production of ROS, and Nrf2 and MAPK (ERK and p38) mediate this induction. Induction of ho-1 may play a role in the protective effects of DAS.
Gong
Pengfei
P
Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.
Hu
Bin
B
Cederbaum
Arthur I
AI
D000498:Allyl Compounds / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D050976:Basic-Leucine Zipper Transcription Factors; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D051547:Heme Oxygenase-1; D018197:Hepatoblastoma / Q000201:enzymology*; D006801:Humans; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013440:Sulfides / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation
D000498:Allyl Compounds; D000970:Antineoplastic Agents; D050976:Basic-Leucine Zipper Transcription Factors; D008565:Membrane Proteins; D009097:Multienzyme Complexes; C117963:NFE2L3 protein, human; D017382:Reactive Oxygen Species; D013440:Sulfides; D014157:Transcription Factors; C038491:allyl sulfide; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D020928:Mitogen-Activated Protein Kinases