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Inhibition of human cytochrome P450 enzymes by the natural hepatotoxin safrole.

YF Ueng — 2007-07-10T04:38:17-00:00

Food Chem Toxicol, Vol. 43, No. 5. (May 2005), pp. 707-712.

The hepatotoxin, safrole is a methylenedioxy phenyl compound, found in sassafras oil and certain other essential oils. Recombinant cytochrome P450 (CYP, P450) and human liver microsomes were studied to investigate the selective inhibitory effects of safrole on human P450 enzymes and the mechanisms of action. Using Escherichia coli-expressed human P450, our results demonstrated that safrole was a non-selective inhibitor of CYP1A2, CYP2A6, CYP2D6, CYP2E1, and CYP3A4 in the IC(50) order CYP2E1 < CYP1A2 < CYP2A6 < CYP3A4 < CYP2D6. Safrole strongly inhibited CYP1A2, CYP2A6, and CYP2E1 activities with IC(50) values less than 20 microM. Safrole caused competitive, non-competitive, and non-competitive inhibition of CYP1A2, CYP2A6 and CYP2E1 activities, respectively. The inhibitor constants were in the order CYP1A2 < CYP2E1 < CYP2A6. In human liver microsomes, 50 microM safrole strongly inhibited 7-ethoxyresorufin O-deethylation, coumarin hydroxylation, and chlorzoxazone hydroxylation activities. These results revealed that safrole was a potent inhibitor of human CYP1A2, CYP2A6, and CYP2E1. With relatively less potency, CYP2D6 and CYP3A4 were also inhibited.

Polymorphism in heme oxygenase-1 (HO-1) promoter is related to the risk of oral squamous cell carcinoma occurring on male areca chewers.

KW Chang — 2007-07-10T04:36:40-00:00

Br J Cancer, Vol. 91, No. 8. (18 October 2004), pp. 1551-1555.

Areca (betel) chewing is associated with the high incidence of oral squamous cell carcinoma (OSCC) and oral submucous fibrosis (OSF) in Asians. Heme oxygenase-1 (HO-1), encoding an oxidative response protein, plays protective roles in cells. A (GT)n microsatellite repeat in HO-1 promoter shows polymorphisms and modulates the level of gene transcription. We examined allelotypic frequencies of (GT)n repeats in 83 controls, 147 OSCC and 71 OSF. All subjects were male areca chewers. Logistic regression was used to adjust the age confounding for odds ratio (OR). (GT)n repeat polymorphism was classified into short (S), medium (M) and long (L) alleles. The adjusted OR in OSCC subjects carrying L allelotype relative to S allelotype was 1.75. Buccal squamous cell carcinoma (BSCC) is the most common OSCC subset in areca chewers. L allelotype implied the risk of BSCC with adjusted OR of 2.05, whereas M allelotype appeared protective for non-BSCC with adjusted OR of 0.49. Our findings indicated that longer (GT)n repeat allele in HO-1 promoter is associated with the risks of areca-related OSCC, while the shorter (GT)n repeat allele may have protective effects for OSCC.

Safrole-DNA adducts in human peripheral blood--an association with areca quid chewing and CYP2E1 polymorphisms.

TY Liu — 2007-07-10T04:35:14-00:00

Mutat Res, Vol. 559, No. 1-2. (11 April 2004), pp. 59-66.

It has been recently demonstrated that safrole (4-allyl-1,2-methylenedioxybenzene)-DNA adducts are present in oral cancer tissue from patients who have chewed areca quid (AQ) containing high concentration of safrole. In this study, the presence of safrole-DNA adducts in peripheral white blood cells from 88 subjects with a known AQ chewing history and 161 matched controls were studied with the aim of identifying the adducts as a biomarker for safrole exposure. This study also analyzed the correlation between the level of safrole-DNA adducts and polymorphism of the CYP2E1 gene, alone and in combination with the GST M1 and GST T1-deletion polymorphisms. The results demonstrated the presence of safrole-DNA adducts in 83 (94.32%) of the DNA samples from subjects with current AQ chewing history and 21 (13.04%) of the control samples without known AQ chewing habit ( [Formula: see text] ). Individuals with at least one CYP2E1 c2 allele had a significant higher frequency of safrole-DNA adducts (odds ratio (OR), 4.00; 95% confidence interval (CI), 1.03-15.53) than those with the CYP2E1 c1c1 genotype while chewing less than 20 areca quids per day. In conclusion, this study demonstrates the presence of safrole-DNA adducts in peripheral blood lymphocytes (PBL), and the presence of these safrole-DNA adducts is correlated with AQ chewing. In addition, the CYP2E1 would seem to play an important role in the modulation of safrole-DNA adduct formation.

Human cytochrome p450 enzyme specificity for bioactivation of safrole to the proximate carcinogen 1'-hydroxysafrole.

SM Jeurissen — 2007-07-10T04:24:46-00:00

Chem Res Toxicol, Vol. 17, No. 9. (September 2004), pp. 1245-1250.

In the present study, the cytochrome P450 mediated bioactivation of safrole to its proximate carcinogenic metabolite, 1'-hydroxysafrole, has been investigated for the purpose of identifying the human P450 enzymes involved. The 1'-hydroxylation of safrole was characterized in a variety of in vitro test systems, including Supersomes, expressing individual human P450 enzymes to a high level, and microsomes derived from cell lines expressing individual human P450 enzymes to a lower, average human liver level. Additionally, a correlation study was performed, in which safrole was incubated with a series of 15 human liver microsomes, and the 1'-hydroxylation rates obtained were correlated with the activities of these microsomes toward specific substrates for nine different isoenzymes. To complete the study, a final experiment was performed in which pooled human liver microsomes were incubated with safrole in the presence and absence of coumarin, a selective P450 2A6 substrate. On the basis of the results of these experiments, important roles for P450 2C9*1, P450 2A6, P450 2D6*1, and P450 2E1 were elucidated. The possible consequences of these results for the effects of genetic polymorphisms and life style factors on the bioactivation of safrole are discussed. Polymorphisms in P450 2C9, P450 2A6, and P450 2D6, leading to poor metabolizer phenotypes, may reduce the relative risk on the harmful effects of safrole, whereas life style factors, such as the use of alcohol, an inducer of P450 2E1, and barbiturates, inducers of P450 2C9, and polymorphisms in P450 2D6 and P450 2A6, leading to ultraextensive metabolizer phenotypes, may increase the relative risk.

Angiotensin-converting enzyme gene insertion/deletion polymorphism is associated with risk of oral precancerous lesion in betel quid chewers.

FM Chung — 2007-07-10T04:18:56-00:00

Br J Cancer, Vol. 93, No. 5. (5 September 2005), pp. 602-606.

To investigate whether angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism is related to the risk of oral precancerous lesions (OPL) in Taiwanese subjects who chew betel quid, a total of 61 betel quid chewers having OPL were compared with 61 asymptomatic betel quid chewers matched for betel quid chewing duration and dosage. The frequency of homozygote for ACE D variant is significantly higher in the case subjects than that of the controls (44.3 vs 24.6%; P = 0.0108). The adjusted odds ratio of the D homozygous for the risk of OPL is 8.10 (95% confidence interval (CI) = 2.04-32.19, P = 0.003). In the allelic base analysis, the D allele is also significantly associated with higher risk of OPL. When grouping the study subjects by smoking status, the association between ACE I/D polymorphism and risk of OPL was only observed in nonsmokers. Our results support the theory that genetic factors may contribute to the susceptibility of OPL and suggest that smoking and genetic factors may be differently involved in the development of OPL.

Ingredients Contribute to Variation in Production of Reactive Oxygen Species by Areca Quid

Ping-Ho Chen — 2006-05-22T02:51:06-00:00

Journal of Toxicology and Environmental Health Part A, Vol. 69, No. 11. (2006), pp. 1055-1069.

Areca Nut Chewing and Mortality in an Elderly Cohort Study

Lan — 2007-03-03T17:02:06-00:00

American Journal of Epidemiology, Vol. 165, No. 6. (15 March 2007), pp. 677-683.