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The Molecular Mechanism of Safrole-induced DNA Adducts and its Role to Oral Carcinogenesis
Liu, Tsung-Yun Korean Environmental Mutagen Society 2003 한국환경성돌연변이·발암원학회지 Vol.23 No.3
IARC classified areca quid as a human carcinogen. Areca quid chewed in Taiwan includes Piper betle inflorescence, which contains high concentrations of safrole (15 mg/fresh weight). Safrole is a documented rodent hepatocarcinogen, and chewing areca quid may contribute to human exposure (420 $\mu$m in saliva). The carcinogenicity of safrole is mediated through 1'-hydroxysafrole formation, followed by sulfonation to an unstable sulfate that reacts to form DNA adducts. Using human liver microsomes and Escherichia coli membranes expressing bicistronic human P450s, CYP2E1 and CYP2C9 were identified as the main P450s involved in the activation of safrole. We have demonstrated the presence of stable safrole-dGMP adducts in human oral tissues following areca quid chewing using $^{32}$ P-postlabeling and HPLC mass spectrometry methods. By studying 88 subjects with a known AQ chewing history and 161 matched controls, we have demonstrated that the presence of safrole-DNA adducts in peripheral blood cells was correlated to AQ chewing, and CYP2E1 seemed to play an important role in the modulation of safrole-DNA adduct formation. We have also shown that safrole can form stable safrole-DNA adducts as well as oxidative damages in rodent liver. However, the stable safrole-DNA adducts may represent a more significant initial lesion as compared to the rapidly repaired safrole-induced 8-hydroxy-2'-deoxyguanosine. This oxidative DNA damage is mediated through the formation of hydoryxchavicol, the major safrole metabolite in human urine. Hydroxychavicol may have gone through two-electron oxidation to the o-quinone; then via one-electron reduction to semiquinone radicals to generate oxidative DNA damage. However, these reactive metabolites can be efficiently conjugated by GSH. These data suggest that safrole may contribute to the initiation of oral carcinogenesis through safrole-DNA adduct and not oxidative DNA damage. In addition, CYP2E1 may modulate this adduct formation.
Liu, Tsung-Yun,Chen, Chiu-Lan,Chung, Yu-Ting,Chi, Chin-Wen The Korean Society of Toxicology Korea Environment 2001 Toxicological Research Vol.17 No.-
Chewing betel quid is associated with an increased risk of oral cancer. The betel quid chewed in Taiwan includes the inflorescence of Piper betle, which contains high concentrations of safrole (15 mg/fresh weight). Piper betle leaf is also used in betel quid; however, the concentration of safrole in betel leaf has not been documented. Chewing betel quid may contribute to safrole exposure in man (420 mm in saliva). Using $a^{32}$P-postlabeling method, we have recently demonstrated the presence of stable safrole-like DNA adducts in human oral tissues following betel quid chewing. Safrole is a rodent hepatocar-cinogen, and the real nature of safrole-DNA adducts in human tissues beside oral has not been elucidated. In this paper, we tested the safrole DNA adducts forming potential in human hepatic and oral derived cells by the ${32}^P$-postlabeling technique. The results suggest that oral cancer derived cell OC-2 alone is not able to form safrole-DNA adduct. However, safrole DNA adducts can be detected following I'-hydroxysafrole, a proximate safrole metabolite, treatment. In addition, pretreament of cytochrome P450 inducers also enhanced the formation of previously undetectable safrole DNA adducts. This finding couples with our previous results suggest that oral may serve as a target tissue for safrole, and safrole may be involved in oral carcinogenesis.
Yun-Ru Liu,El-Wui Loh,Tsung-Ming Hu,Tsuo-Hung Lan,Hsien-Jane Chiu,Yung-Han Chang,Shuo-Fei Chen,Yen-Hsin Yu,Cheng-Chung Chen 대한신경정신의학회 2014 PSYCHIATRY INVESTIGATION Vol.11 No.2
Objective Metabolic abnormalities, e.g., diabetes, are common among schizophrenia patients. Peroxisome proliferator activated receptor-γ (PPAR-γ) regulates glucose/lipid metabolisms, and schizophrenia like syndrome may be induced by actions involving retinoid X receptor-α/PPAR-γ heterodimers. We examined a possible role of the PPAR-γ gene in metabolic traits and psychosis profile in schizophrenia patients exposed to antipsychotics. Methods Single nucleotide polymorphisms (SNPs) of the PPAR-γ gene and a serial of metabolic traits were determined in 394 schizophrenia patients, among which 372 were rated with Positive and Negative Syndrome Scale (PANSS). Results SNP-10, -12, -18, -19, -20 and -26 were associated with glycated hemoglobin (HbA1c) whereas SNP-18, -19, -20 and -26 were associated with fasting plasma glucose (FPG). While SNP-23 was associated with triglycerides, no associations were identified between the other SNPs and lipids. Further haplotype analysis demonstrated an association between the PPAR-γ gene and psychosis profile. Conclusion Our study suggests a role of the PPAR-γ gene in altered glucose levels and psychosis profile in schizophrenia patients exposed to antipsychotics. Although the Pro12Ala at exon B has been concerned an essential variant in the development of obesity, the lack of association of the variant with metabolic traits in this study should not be treated as impossibility or a proof of error because other factors, e.g., genes regulated by PPAR-γ, may have complicated the development of metabolic abnormalities. Whether the PPAR-γ gene modifies the risk of metabolic abnormalities or psychosis, or causes metabolic abnormalities that lead to psychosis, remains to be examined.
( Pei Chuan Tsung ),( Jong Hyeok Park ),( You Sun Kim ),( Sun Young Kim ),( Won Wo Park ),( Hyun Tae Kim ),( Jin Nam Kim ),( Yun Kyung Kang ),( Jeong Seop Moon ) 대한간학회 2013 Gut and Liver Vol.7 No.2
Background/Aims: Mini-probe endoscopic ultrasonography (mEUS) is a useful diagnostic tool for accurate assessment of tumor invasion. The aim of this study was to estimate the accuracy of mEUS in patients with early colorectal cancer (ECC). Methods: Ninety lesions of ECC underwent mEUS for pre-treatment staging. We divided the lesions into either the mucosal group or the submucosal group according to the mEUS findings. The histological results of the specimens were compared with the mEUS findings. Results: The overall accuracy for assessing the depth of tumor invasion (T stage) was 84.4% (76/90). The accuracy of mEUS was significantly lower for submucosal lesions compared to mucosal lesions (p=0.003) and it was lower for large tumors (≥2 cm) (p=0.034). The odds ratios of large tumors and submucosal tumors affecting the accuracy of T staging were 3.46 (95% confidence interval [CI], 1.05 to 11.39) and 6.25 (95% CI, 1.85 to 25.14), respectively. When submucosal tumors were combined with large size, the odds ratio was 14.67 (95% CI, 1.46 to 146.96). Conclusions: The overall accuracy of T stage determination with mEUS was considerably high in patients with ECC; however, the accuracy decreased when tumor size was >2 cm or the tumor had invaded the submucosal layer. (Gut Liver 2013;7:163-168)
총배빈,강경화,홍상훈,김원일,Tsung, Pei-Yun,Kang, Kyung-Hwa,Hong, Sang-Hun,Kim, Won-Il 대한한방안이비인후피부과학회 2007 한방안이비인후피부과학회지 Vol.20 No.1
Object : We investigated the effect of Gamiokyaek-tang(GOYT) on immediate type hypersensitivity. Methods : We investigated anti-dinitrophenyl(DNP) IgE-mediated passive cutaneous anaphylaxis(PCA) and acetic acid-induced vascular permeability in rodents. Also we measured MTT assay, ${\beta}-hexosminidase$ activity and IL-4 from RBL-2H3 and nitric oxide from Raw264.7. Results : GOYT inhibited passive cutaneous anaphylaxis and acetic acid-induced vascular permeability by oral administration. All the concentrations of GOYT from 0.1 to 5mg/ml didn't have an effect on cell viability and cytotoxicity. In RBL-2H3, ${\beta}-hexosminidase$ release and IL-4 production were significantly reduced by 1, 2 and 5mg/ml of GOYT. In Raw264.7, nitric oxide level was decreased by 5mg/ml of GOYT. Conclusion : These results indicate that GOYT have inhibition effects on immediate type hypersensitivity.
Shyh-Yuh Wei,Tsung-Han Tsai,Tsung-Yu Tsai,Po See Chen,Huai-Hsuan Tseng,Yen Kuang Yang,Tianye Zhai,Yihong Yang,Tzu-Yun Wang 대한정신약물학회 2024 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.22 No.1
Objective: The relationship between adverse childhood experiences and methamphetamine use disorder (MUD) has been shown in previous studies; nevertheless, the underlying neural mechanisms remain elusive. Childhood trauma is associated with aberrant functional connectivity (FC) within the default-mode network (DMN). Furthermore, within the DMN, FC may contribute to impaired self-awareness in addiction, while cross-network FC is critical for relapse. We aimed to investigate whether childhood trauma was associated with DMN-related resting-state FC among healthy controls and patients with MUD and to examine whether DMN-related FC affected the effect of childhood trauma on the symptom load of MUD diagnosis. Methods: Twenty-seven male patients with MUD and 27 male healthy controls were enrolled and completed the Childhood Trauma Questionnaire. DMN-related resting-state FC was examined using functional magnetic resonance imaging. Results: There were 47.1% healthy controls and 66.7% MUD patients in this study with adverse childhood experiences. Negative correlations between adverse childhood experiences and within-DMN FC were observed in both healthy controls and MUD patients, while within-DMN FC was significantly altered in MUD patients. The detrimental effects of adverse childhood experiences on MUD patients may be attenuated through DMN-executive control networks (ECN) FC. Conclusion: Adverse childhood experiences were negatively associated with within-DMN FC in MUD patients and healthy controls. However, DMN-ECN FC may attenuate the effects of childhood trauma on symptoms load of MUD.
총배빈,강경화,김원일,Tsung, Pei-Yun,Kang, Kyung-Hwa,Kim, Won-Il 대한한방안이비인후피부과학회 2006 한방안이비인후피부과학회지 Vol.19 No.3
Object : We investigated the effect of Gamiokyaek-tang (GOYT) on immediate type hypersensitivity. Methods : We investigated anti-dinitrophenyl (DNP) IgE-mediated passive cutaneous anaphylaxis and acetic acid-induced vascular permeability in rodents. Also perfonned MTT assay and b-hexosaminidase activity is measured in RBL-2H3. Results : GOYT inhibited passive cutaneous anaphylaxis and acetic acid-induced vascular permeability by oral administration. All the concentrations of GOYT from 0.1 to 5 mg/ml didn't have an effect on cell viability and cytotoxicity. b-hexosaminidase release in RBL-2H3 was significantly reduced by 2 and 5 mg/ml of GOYT. Conclusion : These results indicate that GOYT have inhibition effects on immediate type hypersensitivity .