Inhibition by Allyl Sulfides and Phenethyl Isothiocyanate of Methyl-n-pentylnitrosamine Depentylation by Rat Esophageal Microsomes, Human and Rat CYP2E1, and Rat CYP2A3

Morris, Chantey R.; Chen, Sheng C.; Zhou, Lin; Schopfer, Lawrence M.; Ding, Xinxin; Mirvish, Sidney S.

doi:10.1207/s15327914nc4801_8

Cited by 30 publications

(12 citation statements)

References 28 publications

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“…It alters the metabolism of aflatoxin, possibly by inducing CYP3A2, 2B1, and 2B2, whereas it induces GST-A5 and AFB1-aldehyde reductase only slightly. Significantly, DAS inhibits the activity of rat CYP2E1 and CYP2A3 (51). This effect may account for the protection we have observed in this study.…”

supporting

confidence: 65%

Chemoprotection Against N-Nitrosomethylbenzylamine-Induced Mutation in the Rat Esophagus

Boer¹,

Yang²,

Holcroft³

et al. 2004

Nutrition and Cancer

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Prevention of esophageal cancer may be possible through dietary modification or supplementation. In this study we have investigated the mutation preventive properties of ellagic acid, green tea, and diallyl sulfide (DAS) against the mutagenicity of the nitrosamine N-nitrosomethylbenzylamine (NMBA) in the esophagus of the rat. In addition, the effect of the consumption of ethanol on the mutagenicity of NMBA was examined. NMBA is specific in inducing tumors in the rat esophagus and has been used in many studies investigating the mechanism and the prevention of this cancer. We found that the type of mutations induced by two 2-mg/kg subcutaneous injections of NMBA in the lacI gene of "Big Blue" rats is consistent with that found previously for nitrosamines in other systems and consists of G:C-->A:T transitions. We report that the addition of ellagic acid to the feed, replacing drinking water with green tea, and gavage with DAS significantly reduced the mutagenicity of NMBA. In contrast, the addition of 5% ethanol to the drinking water increased the mutagenicity of NMBA. This is consistent with findings that these compounds modulate NMBA-induced carcinogenesis in the rat.

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supporting

confidence: 65%

Chemoprotection Against N-Nitrosomethylbenzylamine-Induced Mutation in the Rat Esophagus

Boer¹,

Yang²,

Holcroft³

et al. 2004

Nutrition and Cancer

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“…Treatments with vitamin C, BHA, staurosporine, SB600125, and U0126 were initiated 1 h prior to ethanol treatment. However, DAS was pretreated for 15 min, prior to ethanol treatment according to the previous protocol [18]. For control samples, only media or appropriate solvents for each treatment group (alcohol with and without DAS, BHA, vitamin C, SB600125 and U0126) were used at each time point.…”

Section: Methodsmentioning

confidence: 99%

Ethanol-Mediated Regulation of Cytochrome P450 2A6 Expression in Monocytes: Role of Oxidative Stress-Mediated PKC/MEK/Nrf2 Pathway

Jin

Kumar

2012

PLoS ONE

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Cytochrome P450 2A6 (CYP2A6) is known to metabolize nicotine, the major constituent of tobacco, leading to the production of toxic metabolites and induction of oxidative stress that result in liver damage and lung cancer. Recently, we have shown that CYP2A6 is induced by ethanol and metabolizes nicotine into cotinine and other metabolites leading to generation of reactive oxygen species (ROS) in U937 monocytes. However, the mechanism by which CYP2A6 is induced by ethanol is unknown. In this study, we have examined the role of the PKC/Nrf2 pathway (protein kinase C-mediated phosphorylation and translocation of nuclear erythroid 2-related factor 2 to the nucleus) in ethanol-mediated CYP2A6 induction. Our results showed that 100 mM ethanol significantly induced CYP2A6 mRNA and protein (∼150%) and increased ROS formation, and induction of gene expression and ROS were both completely blocked by treatment with either a CYP2E1 inhibitor (diallyl sulfide) or an antioxidant (vitamin C). The results suggest the role of oxidative stress in the regulation of CYP2A6 expression. Subsequently, we investigated the role of Nrf2 pathway in oxidative stress-mediated regulation of CYP2A6 expression in U937 monocytes. Our results showed that butylated hydroxyanisole, a stabilizer of nuclear Nrf2, increased CYP2A6 levels >200%. Staurosporine, an inhibitor of PKC, completely abolished ethanol-induced CYP2A6 expression. Furthermore, our results showed that a specific inhibitor of mitogen-activated protein kinase kinase (MEK) (U0126) completely abolished ethanol-mediated CYP2A6 induction and Nrf2 translocation. Overall, these results suggest that CYP2E1-mediated oxidative stress produced as a result of ethanol metabolism translocates Nrf2 into the nucleus through PKC/MEK pathway, resulting in the induction of CYP2A6 in monocytes. An increased level of CYP2A6 in monocytes is expected to further increase oxidative stress in smokers through CYP2A6-mediated nicotine metabolism. Thus, this study has clinical relevance because of the high incidence of alcohol use among smokers, especially in HIV-infected individuals.

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“…Protecting against DNA damage and, thus, suppressing tumour initiation step is a major importance anticarcinogenic mechanism of isothiocyanates [17]. This can be achieved by reducing the availability of the metabolite products of chemical carcinogens by averting their generation, thus inhibition of their cytochrome P450-mediated bio-activation [18–20], and/or by stimulating their detoxification, via induction of enzyme systems such as the quinone reductase and glutathione S -transferases [21]. Nevertheless, the chemopreventive properties of isothiocyanates at this stage are multiple depending on dose regimen, animal species [22], nature of isothiocyanate [23], target tissue [24], and treatment protocol [25].…”

Section: Introductionmentioning

confidence: 99%

Induction of Epoxide Hydrolase, Glucuronosyl Transferase, and Sulfotransferase by Phenethyl Isothiocyanate in Male Wistar Albino Rats

Razis

Noor

Konsue

2014

BioMed Research International

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Phenethyl isothiocyanate (PEITC) is an isothiocyanate found in watercress as the glucosinolate (gluconasturtiin). The isothiocyanate is converted from the glucosinolate by intestinal microflora or when contacted with myrosinase during the chopping and mastication of the vegetable. PEITC manifested protection against chemically-induced cancers in various tissues. A potential mechanism of chemoprevention is by modulating the metabolism of carcinogens so as to promote deactivation. The principal objective of this study was to investigate in rats the effect of PEITC on carcinogen-metabolising enzyme systems such as sulfotransferase (SULT), N-acetyltransferase (NAT), glucuronosyl transferase (UDP), and epoxide hydrolase (EH) following exposure to low doses that simulate human dietary intake. Rats were fed for 2 weeks diets supplemented with PEITC at 0.06 µmol/g (low dose, i.e., dietary intake), 0.6 µmol/g (medium dose), and 6.0 µmol/g (high dose), and the enzymes were monitored in rat liver. At the Low dose, no induction of the SULT, NAT, and EH was noted, whereas UDP level was elevated. At the Medium dose, only SULT level was increased, whereas at the High dose marked increase in EH level was observed. It is concluded that PEITC modulates carcinogen-metabolising enzyme systems at doses reflecting human intake thus elucidating the mechanism of its chemoprevention.

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Inhibition by Allyl Sulfides and Phenethyl Isothiocyanate of Methyl-n-pentylnitrosamine Depentylation by Rat Esophageal Microsomes, Human and Rat CYP2E1, and Rat CYP2A3

Cited by 30 publications

References 28 publications

Chemoprotection Against N-Nitrosomethylbenzylamine-Induced Mutation in the Rat Esophagus

Chemoprotection Against N-Nitrosomethylbenzylamine-Induced Mutation in the Rat Esophagus

Ethanol-Mediated Regulation of Cytochrome P450 2A6 Expression in Monocytes: Role of Oxidative Stress-Mediated PKC/MEK/Nrf2 Pathway

Induction of Epoxide Hydrolase, Glucuronosyl Transferase, and Sulfotransferase by Phenethyl Isothiocyanate in Male Wistar Albino Rats

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