Inhibition of cytochrome P-450 2E1 by diallyl sulfide and its metabolites

Brady, John F.; Ishizaki, Hiroyuki; Fukuto, Jon M.; Lin, Marie C.M.; Fadel, Addi R.; Gapac, Jeanne M.; Yang, Chung S.

doi:10.1021/tx00024a008

Cited by 248 publications

(144 citation statements)

References 13 publications

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“…We initially hypothesized that CC14 metabolism and lipid peroxidation contribute to hepatocyte death in culture. However, in our system two different inhibitors of P450, cimetidine and diallyl sulfide (Nanji et al 1994;Brady et al 1991) reduced isoprostane accumulation by >8O%, almost to control levels, without an evident decrease in cell death. Kupffer cells probably also play an important role in promoting CC14 toxicity in vivo (Edwards et al 1993).…”

Section: Discussionmentioning

confidence: 54%

Mechanism of Early Carbon Tetrachloride Toxicity in Cultured Rat Hepatocytes

Johnston

Kroening

1998

Pharmacology & Toxicology

121

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CCl, causes liver necrosis in a dose-dependent manner in v i m However, we found that primary rat hepatocytes in culture were killed after a 2 hr incubation with carbon tetrachloride gas at CC14 partial pressures above a threshold between 45 and 54 mmHg. Below this threshold concentration no increase in hepatocyte death was observed. We sought to explain the very abrupt C C 4 concentration threshold for hepatocyte death. Two inhibitors of cytochrome P450 2E1, cimetidine and diallyl sulfide, inhibited lipid peroxidation as measured by production of isoprostanes, but did not reduce hepatocyte death from CC4. At 37", CCI, accelerated the mitochondrial permeability transition in vitro, at a threshold C C 4 concentration similar to that which caused hepatocyte death. Phospholipase A2 inhibitors, mepacrine and 4bromo-phenacyl bromide, inhibited the increase in mitochondria1 permeability, but did not inhibit hepatocyte death caused by CC,. Rat liver microsomal lipids were used to make liposomes loaded with Ponceau Red (FW 760.6). No leakage of Ponceau red was found at CCI, concentrations greater than the threshold for cell death. However, CC4 caused acceleration of liposome fusion, over the C C 4 concentration range spanning the threshold for hepatocyte death. Early hepatocyte death in cell culture is independent of metabolism of CC,, and may be related to direct effects of CC14 on intracellular membranes.

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Section: Discussionmentioning

confidence: 54%

Mechanism of Early Carbon Tetrachloride Toxicity in Cultured Rat Hepatocytes

Johnston

Kroening

1998

Pharmacology & Toxicology

121

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“…Nitrile dose selection was based on our previous data Saldaña-Ruíz et al 2012a). The selective CYP2E1 inhibitor DAS (Brady et al 1991) was administered p.o. in 6 ml/kg of corn oil; DAS acts as a competitive inhibitor of CYP2E1 and is also metabolized to suicide inhibitors of the same enzyme.…”

Section: Dosing and Experimental Protocolmentioning

confidence: 99%

Reduced Systemic Toxicity and Preserved Vestibular Toxicity Following Co-treatment with Nitriles and CYP2E1 Inhibitors: a Mouse Model for Hair Cell Loss

Saldaña-Ruíz

Boadas-Vaello

Sedó-Cabezón

et al. 2013

JARO

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Several nitriles, including allylnitrile and ciscrotononitrile, have been shown to be ototoxic and cause hair cell degeneration in the auditory and vestibular sensory epithelia of mice. However, these nitriles can also be lethal due in large part to the microsomal metabolic release of cyanide, which is mostly dependent on the activity of the 2E1 isoform of the cytochrome P450 (CYP2E1). In this study, we co-administered mice with a nitrile and, to reduce their lethal effects, a selective CYP2E1 inhibitor: diallylsulfide (DAS) or trans-1,2-dichloroethylene (TDCE). Both in female 129S1/SvImJ (129S1) mice co-treated with DAS and cis-crotononitrile and in male RjOrl:Swiss/CD-1 (Swiss) mice co-treated with TDCE and allylnitrile, the nitrile caused a dose-dependent loss of vestibular function, as assessed by a specific behavioral test battery, and of hair cells, as assessed by hair bundle counts using scanning electron microscopy. In the experiments, the CYP2E1 inhibitors provided significant protection against the lethal effects of the nitriles and did not diminish the vestibular toxicity as assessed by behavioral effects in comparison to animals receiving no inhibitor. Additional experiments using a single dose of allylnitrile demonstrated that TDCE does not cause hair cell loss on its own and does not modify the vestibular toxicity of the nitrile in either male or female 129S1 mice. In all the experiments, high vestibular dysfunction scores in the behavioral test battery predicted extensive to complete loss of hair cells in the utricles. This provides a means of selecting animals for subsequent studies of vestibular hair cell regeneration or replacement.

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“…A growing number of naturally occurring phytochemicals in foods and herbal supplements have been shown to be substrates or inactivators of P450 enzymes. Some examples include bergamottin, a component of grapefruit juice (He et al, 1998); capsaicin from chili peppers (Surh and Lee, 1995); diallylsulfide found in garlic oil (Brady et al, 1991); numerous isothiocyanates found in all cruciferous vegetables (Conaway et al, 1996;Goosen et al, 2000); I3,II8-bia-piogenin, hypericin, hyperforin, and other components of St. John's Wort (Orbach, 2000); roquefortine, a secondary cyclopeptide metabolite generated by Penicillium reoquefortine and other Penicillium species (Aniant et al, 2001); reservatol, a component of red wine (Chan and Delucchi, 2000); and thujones found in the liqueur absinthe (Höld et al, 2001).…”

Section: Liver Microsomal P450mentioning

confidence: 99%

The Licorice Root Derived Isoflavan Glabridin Inhibits the Activities of Human Cytochrome P450S 3A4, 2B6, and 2C9

Kent¹,

Aviram²,

Rosenblat³

et al. 2002

Drug Metab Dispos

130

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ABSTRACT:The potent antioxidants licorice root extract and glabridin, an isoflavan purified from licorice root extract, were tested for their ability to modulate the activities of several cytochrome P450 (P450) enzymes. P450 3A4, the major human drug metabolizing P450 enzyme, was inactivated by licorice root extract and by glabridin in a time-and concentration-dependent manner. The inactivation was NADPH-dependent and was not reversible by extensive dialysis. Further analysis showed that the loss in enzymatic activity correlated with a loss in the P450-reduced CO spectrum and with a loss of the intact heme moiety. In contrast, incubations of P450 3A4 with similar concentrations of 2,4-dimethylglabridin and NADPH did not lead to inactivation of P450 3A4. P450 2B6 was also inactivated by glabridin in a time-and concentration-dependent manner. The majority of the glabridin-inactivated P450 2B6 was able to form a reduced CO spectrum suggesting that the heme was not modified with this isoform. High-performance liquid chromatography analysis of the P450 heme confirmed that incubations with glabridin and NADPH did not result in the destruction of the heme moiety. The activity of P450 2C9 was competitively inhibited by glabridin, whereas P450 2D6 and P450 2E1 were virtually unaffected. The data show that glabridin can serve as a substrate for at least three human P450 enzymes and that depending on the isoform, metabolism of glabridin can lead to mechanism-based inactivation or inhibition of the P450. Heme and reduced CO spectral analysis also indicated that glabridin inactivated P450s 2B6 and 3A4 by different mechanisms. Liver microsomal P4501 enzymes are involved in the metabolism of endogenous substrates such as fatty acids, cholesterol, and steroids. These enzymes also carry out an important function in the catalysis and ultimate clearance of many structurally distinct xenobiotics such as drugs, pesticides, carcinogens, and environmental pollutants (Porter and Coon, 1991; Rendic and DiCarlo, 1997). P450 3A4, the major hepatic and intestinal P450 enzyme in humans, metabolizes more than 50% of clinically used drugs such as cyclosporine A, dihydropyridines, ethynylestradiol, midazolam, terfenadine, and triazolam. On average, P450 2B6 comprises approximately 0.2% of human liver P450 and is responsible for the metabolism of roughly 3% of all drugs such as ketamine (Yanagihara et al., 2001), orphenadrine, secobarbital, phenobarbital, dexamethasone, and rifampin (Chang et al., 1997). The P450 2C family comprises approximately 18% of the P450 enzymes found in human liver and are responsible for the metabolism of at least 25% of all drugs including tolbutamide, diclofenac, (S)-warfarin, phenytoin, and hexobarbital.

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Inhibition of cytochrome P-450 2E1 by diallyl sulfide and its metabolites

Cited by 248 publications

References 13 publications

Mechanism of Early Carbon Tetrachloride Toxicity in Cultured Rat Hepatocytes

Mechanism of Early Carbon Tetrachloride Toxicity in Cultured Rat Hepatocytes

Reduced Systemic Toxicity and Preserved Vestibular Toxicity Following Co-treatment with Nitriles and CYP2E1 Inhibitors: a Mouse Model for Hair Cell Loss

The Licorice Root Derived Isoflavan Glabridin Inhibits the Activities of Human Cytochrome P450S 3A4, 2B6, and 2C9

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