Safrole-DNA adducts in tissues from esophageal cancer patients: clues to areca-related esophageal carcinogenesis.
Epidemiological studies have demonstrated that areca quid chewing can be an independent risk factor for developing esophageal cancer. However, no studies are available to elucidate the mechanisms of how areca induces carcinogenesis in the esophagus. Since the areca nut in Taiwan contains a high concentration of safrole, a well-known carcinogenic agent, we analyzed safrole-DNA adducts by the 32P-postlabelling method in tissue specimens from esophageal cancer patients. In total, we evaluated 47 patients with esophageal cancer (16 areca chewers and 31 non-chewers) who underwent esophagectomy at the National Taiwan University Hospital between 1996 and 2002. Of the individuals with a history of habitual areca chewing (14 cigarette smokers and two non-smokers), one of the tumor tissue samples and five of the normal esophageal mucosa samples were positive for safrole-DNA adducts. All patients positive for safrole-DNA adducts were also cigarette smokers. Such adducts could not be found in patients who did not chew areca, irrespective of their habits of alcohol consumption or cigarette smoking (p<0.001, comparing the areca chewers with non-chewers). The genotoxicity of safrole was also tested in vitro in three esophageal cell lines and four cultures of primary esophageal keratinocytes. In two of the esophageal keratinocyte cultures, adduct formation was increased by treatment with safrole after induction of cytochrome P450 by 3-methyl-cholanthrene. This paper provides the first observation of how areca induces esophageal carcinogenesis, i.e., through the genotoxicity of safrole, a component of the areca juice.
Lee
Jang-Ming
JM
Department of Surgery, National Taiwan University Hospital, 7, Chung-Shang South Road, Taipei, Taiwan, ROC. ntuhlee@yahoo.com
Liu
Tsung-Yung
TY
Wu
Deng-Chyang
DC
Tang
Hseau-Chung
HC
Leh
Julie
J
Wu
Ming-Tsang
MT
Hsu
Hsao-Hsun
HH
Huang
Pei-Ming
PM
Chen
Jin-Shing
JS
Lee
Chun-Jean
CJ
Lee
Yung-Chie
YC
D000368:Aged; D000428:Alcohol Drinking; D000818:Animals; D001114:Areca / Q000737:chemistry / Q000633:toxicity*; D002460:Cell Line; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism*; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004947:Esophagus / Q000473:pathology; D005260:Female; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009152:Mutagenicity Tests; D012307:Risk Factors; D012451:Safrole / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D012907:Smoking; D013624:Taiwan
D018736:DNA Adducts; D012451:Safrole