Hydroxychavicol modulates benzo[a]pyrene-induced genotoxicity through induction of dihydrodiol dehydrogenase.
Areca quid (AQ) chewing and smoking have synergistic potential in the development of oral squamous cell carcinoma (OSCC). In Taiwan, fresh Piper betle inflorescence is uniquely added to AQ, and hydroxychavicol (HC) is the major phenolic component of P. betle inflorescence. This study investigated whether HC modulates cigarette carcinogen benzo[a]pyrene (B[a]P)-mediated toxic effects. Pretreatment of HC and followed by B[a]P challenge resulted in higher cytotoxicity and HPRT gene mutation frequency (P < 0.05). However, this treatment protocol resulted in decreased bulky B[a]P-DNA adduct levels as demonstrated by 32P-postlabeling technique (P < 0.05). Western blotting analysis indicated that HC pretreatment induced the expression of cyclooxygenase-2 (COX-2) and dihydrodiol dehydrogenase (DDH). COX-2 is know to participate in the B[a]P-DNA adduct formation, while DDH has been shown to divert B[a]P-diol to B[a]P-7,8-quinone and the generation of reactive oxygen species (ROS). Using flow cytometry, this study demonstrated the increased production of 8-oxoguanine (P < 0.001). Overall, the results suggest that HC-induced DDH is more important than site-by-site up-regulation of COX-2 in B[a]P-induced cytotoxicity and HPRT gene mutation. Furthermore, DDH-mediated oxidative DNA damage and not B[a]P-DNA adduct formation may be involved in the HC and B[a]P-induced toxic effects.
Tang
Deh-Wei
DW
Institutes of Pharmacology, National Yang-Ming University, Taipei, Taiwan, ROC.
Chang
Kuo-Wei
KW
Chi
Chin-Wen
CW
Liu
Tsung-Yun
TY
D001114:Areca / Q000009:adverse effects* / Q000737:chemistry*; D001564:Benzo(a)pyrene / Q000633:toxicity*; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity*; D002294:Carcinoma, Squamous Cell / Q000209:etiology / Q000473:pathology*; D051546:Cyclooxygenase 2; D018736:DNA Adducts; D004249:DNA Damage; D004347:Drug Interactions; D004790:Enzyme Induction; D005054:Eugenol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis; D008565:Membrane Proteins; D009062:Mouth Neoplasms / Q000209:etiology / Q000473:pathology*; D010088:Oxidoreductases / Q000096:biosynthesis*; D031721:Piper betle / Q000737:chemistry*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
D002273:Carcinogens; D018736:DNA Adducts; D007527:Isoenzymes; D008565:Membrane Proteins; C051268:2-hydroxychavicol; D001564:Benzo(a)pyrene; D005054:Eugenol; D010088:Oxidoreductases; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C048338:trans-1,2-dihydrobenzene-1,2-diol dehydrogenase