Induction of Forestomach Lesions by Butylhydroxyanisole and Structurally Related Substances

Altmann, Hans; Grunow, W.; Wester, P.W.; Möhr, U.

doi:10.1007/978-3-642-69928-3_14

Cited by 20 publications

(12 citation statements)

References 3 publications

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“…235 Only mild forestomach hyperplastic responses were present in rats fed 2% HQ for 4 weeks. 236 Taken together, these results do not support a significant potential for HQ to induce gastrointestinal neoplasia in rodent bioassays.…”

Section: Other Data Related To Carcinogenesismentioning

confidence: 74%

The Toxicology of Hydroquinone — Relevance to Occupational and Environmental Exposure

DeCaprio¹

1999

Critical Reviews in Toxicology

175

128

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Hydroquinone (HQ) is a high-volume commodity chemical used as a reducing agent, antioxidant, polymerization inhibitor, and chemical intermediate. It is also used in over-the-counter (OTC) drugs as an ingredient in skin lighteners and is a natural ingredient in many plant-derived products, including vegetables, fruits, grains, coffee, tea, beer, and wine. While there are few reports of adverse health effects associated with the production and use of HQ, a great deal of research has been conducted with HQ because it is a metabolite of benzene. Physicochemical differences between HQ and benzene play a significant role in altering the pharmacokinetics of directly administered when compared with benzene-derived HQ. HQ is only weakly positive in in vivo chromosomal assays when expected human exposure routes are used. Chromosomal effects are increased significantly when parenteral or in vitro assays are used. In cancer bioassays, HQ has reproducibly produced renal adenomas in male F344 rats. The mechanism of tumorigenesis is unclear but probably involves a species-, strain-, and sex-specific interaction between renal tubule toxicity and an interaction with the chronic progressive nephropathy that is characteristic of aged male rats. Mouse liver tumors (adenomas) and mononuclear cell leukemia (female F344 rat) have also been reported following HQ exposure, but their significance is uncertain. Various tumor initiation/promotion assays with HQ have shown generally negative results. Epidemiological studies with HQ have demonstrated lower death rates and reduced cancer rates in production workers when compared with both general and employed referent populations. Parenteral administration of HQ is associated with changes in several hematopoietic and immunologic endpoints. This toxicity is more severe when combined with parenteral administration of phenol. It is likely that oxidation of HQ within the bone marrow compartment to the semiquinone or p-benzoquinone (BQ), followed by covalent macromolecular binding, is critical to these effects. Bone marrow and hematologic effects are generally not characteristic of HQ exposures in animal studies employing routes of exposure other than parenteral. Myelotoxicity is also not associated with human exposure to HQ. These differences are likely due to significant route-dependent toxicokinetic factors. Fetotoxicity (growth retardation) accompanies repeated administration of HQ at maternally toxic dose levels in animal studies. HQ exposure has not been associated with other reproductive and developmental effects using current USEPA test guidelines. The skin pigment lightening properties of HQ appear to be due to inhibition of melanocyte tyrosinase. Adverse effects associated with OTC use of HQ in FDA-regulated products have been limited to a small number of cases of exogenous ochronosis, although higher incidences of this syndrome have been reported with inappropriate use of unregulated OTC products containing higher HQ concentrations. The most serious human health effect related to HQ is p...

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Section: Other Data Related To Carcinogenesismentioning

confidence: 74%

The Toxicology of Hydroquinone — Relevance to Occupational and Environmental Exposure

DeCaprio¹

1999

Critical Reviews in Toxicology

175

128

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“…In cells transfected with Trx2 overexpressing vectors, tBHQ-initiated induction was blocked, showing no significant changes from untreated cultures. Asterisks denote a statistically significant difference (p<0.05) from empty vector controls treated at the same concentration of tBHQ colon adenocarcinomas, hepatocellular carcinomas, and liver preneoplastic foci in animal models (Fukushima et al 1991;Hasegawa et al 1992;Hirose et al 1993), but tBHQ is also associated with esophageal hyperplasia, forestomach papillomas, and hyperplasia of mucosa (Altmann et al 1985;Hirose et al 1993). While much of tBHQ protection, and possibly its carcinogenic effect, is believed to be the consequence of ROS generation via quinone/semiquinone redox cycling, our results showed very little cellular ROS production, but rather very discrete ROS production within the mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Tert-butylhydroquinone induces mitochondrial oxidative stress causing Nrf2 activation

Imhoff

Hansen

2010

Cell Biol Toxicol

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Tert-butylhydroquinone (tBHQ), the major metabolite of butylated hydroxyanisole, induces an antioxidant response through the redox-sensitive transcription factor, nuclear factor-E2-related factor-2 (Nrf2). However, the mechanism by which tBHQ induces Nrf2 activity is not entirely understood. Here, we show that tBHQ preferentially alters the redox status in the mitochondrial compartment in HeLa cells. HeLa cells treated with tBHQ showed a preferential oxidation of mitochondrial thioredoxin-2 (Trx2), while cellular glutathione and cytosolic thioredoxin-1 were not affected. Preferential mitochondrial oxidation by tBHQ was supported by detection of reactive oxygen species (ROS) specific to this compartment. To determine the role of Trx2 in regulating downstream effects of tBHQ, HeLa cells were transiently transfected with an empty, Trx2, or C93S (Cys93Ser) Trx2 dominant-negative mutant expression vector. Overexpression of Trx2 decreased basal mitochondrial ROS production, whereas expression of C93S Trx2 enhanced it. In addition, under untreated conditions, expression of C93S Trx2 led to an increase in the basal activities of Nrf2. With tBHQ treatments, Trx2 overexpression suppressed Nrf2 accumulation and activity, whereas expression of C93S Trx2 had no effect on the degree of inducibility or Nrf2 accumulation but did increase the overall activity of Nrf2. Quantitative polymerase chain reaction analysis of Nrf2-regulated gene expression corroborate Trx2 control of tBHQ-mediated Nrf2 activation. These data show a compartment-specific effect where tBHQ-induced Nrf2 signaling is mediated by Trx2 and suggest that antioxidant status in various compartments would provide different levels of control of redox signaling.

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“…In several instances, these histological changes have preceded forestomach tumor development in chronic studies (Altmann et al 1985;Ghanayem et al 1986). According to the Hazardous Substances Data Bank on TOXNET, this forestomach lesion has been associated with approximately 181 chemicals, but only with the oral route of administration.…”

Section: Introductionmentioning

confidence: 98%

Acetaminophen-Induced Forestomach Lesion in Normal Rats Following Intravenous Exposure

McKee

Gass

2011

Toxicol Pathol

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Four groups of ten male and ten female rats each were treated intravenously with saline, 400 mg/kg/day of a commercially available injectable acetaminophen formulation, or 400 mg/kg/day of a new injectable acetaminophen formulation with (aged) or without (fresh) impurities daily for fourteen days. Gross observations of the mucosal surface of the stomachs from treated rats included multifocal to diffuse pale, elevated foci confined to the nonglandular region of the stomach. Treatment-related histologic observations consisted of epithelial hyperplasia and hyperkeratosis of the nonglandular mucosa of the stomach. The epithelial hyperplasia was characterized by a thickened epithelium, frequently accompanied by the development of undulations at the basement membrane zone, resulting in the formation of rete ridgelike structures protruding into the underlying tissue. The submucosa was usually expanded by edema and occasionally contained an infiltrate of neutrophils, eosinophils, and macrophages. The hyperplasia was usually accompanied by hyperkeratosis resulting in thickening of the stratum corneum. The incidence and severity of the gastric changes were similar across all treatment regimens. Although considered clinically irrelevant since humans do not have a forestomach equivalent, these results are significant in that this appears to be the first report of forestomach hyperplasia and hyperkeratosis following intravenous exposure to acetaminophen.

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Induction of Forestomach Lesions by Butylhydroxyanisole and Structurally Related Substances

Cited by 20 publications

References 3 publications

The Toxicology of Hydroquinone — Relevance to Occupational and Environmental Exposure

The Toxicology of Hydroquinone — Relevance to Occupational and Environmental Exposure

Tert-butylhydroquinone induces mitochondrial oxidative stress causing Nrf2 activation

Acetaminophen-Induced Forestomach Lesion in Normal Rats Following Intravenous Exposure

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