Biochemical effects of dithiolthiones

Ansher, Sherry S.; Dolan, Patrick; Bueding, Ernest

doi:10.1016/0278-6915(86)90205-x

Cited by 142 publications

(57 citation statements)

References 15 publications

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“…It has been proposed that induction of phase 2 detoxifying enzyme genes plays a major role in protection against carcinogens (18). A recognized characteristic action of chemopreventive agents, including the phenolic antioxidants 2,3-butyl-4-hydroxyanisole (19) and 1,2-dithiole-3-thione (20) and the isothiocyanates (21), is their potential to induce phase 2 enzymes. Oltipraz (4-methyl-5-[2-pyrazinyl]-1,2-dithiole-3-thione) represents one of the most potent inducers of phase 2 enzymes (22,23).…”

Section: Introductionmentioning

confidence: 99%

Nrf2 Is Essential for the Chemopreventive Efficacy of Oltipraz against Urinary Bladder Carcinogenesis

Itoh²,

et al. 2004

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The induction of phase 2 detoxifying enzymes, such as UDP-glucuronosyltransferases (UGTs), in response to an array of naturally occurring and synthetic agents, such as oltipraz (4-methyl-5-[2-pyrazinyl]-1,2-dithiole-3-thione), provides an effective means of protection against a variety of carcinogens. Transcription factor Nrf2 is an essential regulator of the inducible expression of detoxifying enzyme genes by chemopreventive agents. In this study, we investigated in Nrf2-deficient mice the susceptibility to the urinary bladder-specific carcinogen N-nitrosobutyl(4-hydroxybutyl)amine (BBN) and the chemopreventive efficacy of oltipraz. The incidence of urinary bladder carcinoma by BBN was significantly higher in Nrf2 ؊/؊ mice than in wild-type mice; invasive carcinoma was found in 24.0 and 38.5% of wild-type and Nrf2 ؊/؊ mice, respectively. Oltipraz induced the phase 2 enzymes responsible for BBN detoxification in the liver and urinary bladder in an Nrf2-dependent manner. As expected, therefore, oltipraz decreased the incidence of urinary bladder carcinoma by BBN in wild-type mice but had little effect in Nrf2 ؊/؊ mice. In wild-type mouse liver, oltipraz significantly induced BBN glucuronidation and decreased the urinary concentration of N-nitrosobutyl(3-carboxypropyl)amine, a proximate carcinogen of BBN. Importantly, BBN was found to suppress the expression of UGT1A specifically in the urinary bladder. This suppression was counteracted by oltipraz in wild-type mice but not in Nrf2 ؊/؊ mice. These results show that Nrf2 and its downstream target genes are responsible for BBN detoxification. Furthermore, oltipraz prevents carcinogenesis by BBN by enhancing detoxification of this carcinogen in the liver and urinary bladder.

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Section: Introductionmentioning

confidence: 99%

Nrf2 Is Essential for the Chemopreventive Efficacy of Oltipraz against Urinary Bladder Carcinogenesis

Itoh²,

et al. 2004

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“…The mechanism of oltipraz action appears to be through elevation of the activity of various detoxicating enzymes, at least in part through transcriptional induction (27,28). In the aflatoxin B 1 model, oltipraz results in higher liver GSH transferase activity, which in turn increases the rate of AFB 1 metabolism, and decreases the formation of AFB 1 -DNA adducts (27,29). Administration of oltipraz to mice also protects against the acute hepatotoxicity associated with acetaminophen and carbon tetrachloride exposure (30).…”

Section: Introductionmentioning

confidence: 99%

Modulation of gene expression in subjects at risk for colorectal cancer by the chemopreventive dithiolethione oltipraz.

Szarka²,

Yao³

et al. 1996

J. Clin. Invest.

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Prolonged exposure to mutagenic substances is strongly associated with an individual's risk of developing colorectal cancer. Clinical investigation of oltipraz as a chemopreventive agent is supported by its induction of the expression of detoxication enzymes in various tissues, and its protective activity against the formation of chemically induced colorectal tumors in animals. The goals of the present study were: to determine if oltipraz could induce detoxicating gene expression in human tissues; to identify effective nontoxic doses for more extensive clinical testing; and to establish a relationship between effects in the colon mucosa and those in a more readily available tissue, the peripheral mononuclear cell. 24 evaluable patients at high risk for colorectal cancer were treated in a dose-finding study with oltipraz 125, 250, 500, or 1,000 mg/m 2 as a single oral dose. Biochemical analysis of sequential blood samples and colon mucosal biopsies revealed increases in glutathione transferase activity at the 1ower dose levels. These effects were not observed at the higher doses. More pronounced changes were observed in detoxicating enzyme gene expression in both tissues at all doses. Peripheral mononuclear cell and colon mRNA content for ␥ -glutamylcysteine synthetase ( ␥ -GCS) and DT-diaphorase increased after dosing to reach a peak on day 2-4 after treatment, and declined to baseline in the subsequent 7-10 d. The extent of induction of gene expression in colon mucosa reached a peak of 5.75-fold for ␥ -GCS, and a peak of 4.14-fold for DT-diaphorase at 250 mg/m 2 ; higher doses were not more effective. Levels of ␥ -GCS and DT-diaphorase correlated closely ( P Յ 0.001) between peripheral mononuclear cells and colon mucosa both at baseline and at peak. These findings demonstrate that the administration of minimally toxic agents at low doses may modulate the expression of detoxicating genes in the tissues of individuals at high risk for cancer. Furthermore, peripheral mononuclear cells may be used as a noninvasive surrogate endpoint biomarker for the transcriptional response of normal colon mucosa to drug administration. ( J. Clin. Invest. 1996. 98:1210-1217.)

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“…The antitumorigenic activity of OPZ is generally ascribed to its strong induction of enzymes that mediate detoxication processes. Early studies revealed that OPZ increases expression of a number of Phase I and II enzymes, including glutathione-S-transferases (GSTs), NAD(P)H:quinone oxidoreductase (NQO1), microsomal epoxide hydrolase, aflatoxin aldehyde reductase, glucuronosyl transferases, as well as enzymes that increase glutathione levels, namely, glutathione reductase and glucose-6-phosphate dehydrogenase (Kensler et al, 1985;Ansher et al, 1986;Davidson et al, 1990;Morel et al, 1993;Primiano et al, 1996).…”

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confidence: 99%

The Nrf2 Activator Oltipraz Also Activates the Constitutive Androstane Receptor

et al. 2008

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ABSTRACT:Oltipraz (OPZ) is a well known inducer of NAD(P)H:quinone oxidoreductase (NQO1) along with other enzymes that comprise the nuclear factor E2-related factor 2 (Nrf2) battery of detoxification genes. However, OPZ treatment also induces expression of CYP2B, a gene regulated by the constitutive androstane receptor (CAR). Therefore, this study was designed to determine whether OPZ induces gene expression in the mouse liver through activation of CAR in addition to Nrf2. OPZ increased the mRNA expression of both Cyp2b10 and Nqo1 in C57BL/6 mouse livers. As expected, in livers from Nrf2

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Biochemical effects of dithiolthiones

Cited by 142 publications

References 15 publications

Nrf2 Is Essential for the Chemopreventive Efficacy of Oltipraz against Urinary Bladder Carcinogenesis

Nrf2 Is Essential for the Chemopreventive Efficacy of Oltipraz against Urinary Bladder Carcinogenesis

Modulation of gene expression in subjects at risk for colorectal cancer by the chemopreventive dithiolethione oltipraz.

The Nrf2 Activator Oltipraz Also Activates the Constitutive Androstane Receptor

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