Hepatic responses to the administration of high doses of BHT to the rat: Their relevance to hepatocarcinogenicity

Powell, C.J.; Connelly, John C.; Jones, S.; Grasso, P.; Bridges, James W.

doi:10.1016/0278-6915(86)90299-1

Cited by 57 publications

(16 citation statements)

References 23 publications

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“…BHT is also an effective inducer of epoxide hydrolase (Powell et al, 1986), an enzyme involved in the detoxication of highly reactive, often short-lived, epoxides. Although methapyrilene epoxide products have yet to be isolated, a thiophene ring substituent of the molecule, which is a candidate toxic metabolite (Singer et al, 1987;Kammerer et al, 1988;Wrighton et al, 1991), may, like other thiophene rings (Bray et al, 1971;Dansette et al, 1990Dansette et al, , 1992, undergo epoxidation.…”

Section: Discussionmentioning

confidence: 99%

Effects of Induction and Inhibition of Cytochromes P450 on the Hepatotoxicity of Methapyrilene

Ratra¹

1998

Toxicological Sciences

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The mechanisms by which the antihistamine drug methapyrilene causes acute periportal hepatotoxicity in rats are not yet elucidated. This study investigated the effects of modulators of cytochrome P450 (CYP) activity on the hepatotoxicity of methapyrilene and also the effect of methapyrilene on hepatic CYP. Pretreatment of male Han Wistar rats with p-naphthoflavone, phenobarbitone, butylated hydroxytoluene, piperonyl butoxide, Aroclor 1254, or cobalt protoporphyrin IX, agents known to modify hepatic CYP, all afforded some degree of protection against a hepatotoxic dose of methapyrilene (150 mg/kg x 3 days p.o.), as assessed by clinical chemistry and histology. Total hepatic CYP depletion by cobalt protoporphyrin IX treatment indicated CYPmediated bioactivation was a prerequisite for methapyrilene-induced hepatotoxicity. Protection against hepatic damage was strongly associated with /3-naphthoflavone induction of CYP1A and phenobarbitone-associated CYP2B induction. However, the role of CYP3A, which is constitutively expressed in the liver and induced by piperonyl butoxide, butylated hydroxytoluene, or Aroclor 1254, was unclear. Modulation of FAD monooxgenase activity by methimazole pretreatment was not associated with increased methapyrilene-induced hepatotoxicity. Methapyrilene treatment alone specifically decreased microsomal enzyme activity markers for CYP2C11, CYP3A, and CYP2A and pretreatment with all the hepatic enzyme-inducing agents specifically prevented the loss of CYP2C11. Together this suggested that CYP2C11 was responsible for the suicide substrate bioactivation of methapyrilene and the toxicologic outcome largely relied upon an abundance of detoxifying enzymes present in the liver, o Methapyrilene is an ethylenediamine H, histamine receptor antagonist which has been used for over 20 years, principally as a sleep aid and in cold and allergy formulations. Subsequently, methapyrilene was withdrawn from clinical use when it was found to be hepatocarcinogenic, following chronic administration in rats (Lijinsky et ai, 1980), although not in 'To whom correspondence should be addressed. Fax: 0171 982 6135. E-mail: c.j.powell@mds.qmw.ac.uk. mice, guinea pigs, or hamsters (Brennan and Creasia, 1982; Lijinsky et ai, 1983). In the rat, acute administration of methapyrilene has been found to damage the periportal region of the liver (Graichen et ai, 1985); however, the underlying biochemical mechanisms responsible are poorly understood.Methapyrilene undergoes extensive metabolism in vivo, in cultured hepatocytes and in microsomes Schmitz, 1986, 1987; Singer et ai, 1987;Kelly et al., 1992). While many metabolites of methapyrilene have been identified, the metabolite(s) responsible for hepatic damage in rats remains elusive. Species differences in the metabolism of methapyrilene seem largely quantitative rather than qualitative (Kammerer and Schmitz, 1987;Lampe and Kammerer, 1990). It is plausible, therefore, that the species differences in methapyrilene-induced hepatotoxicity may be explained by differences in ...

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Section: Discussionmentioning

confidence: 99%

Effects of Induction and Inhibition of Cytochromes P450 on the Hepatotoxicity of Methapyrilene

Ratra¹

1998

Toxicological Sciences

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“…Although the issue is far from being resolved, there is growing pressure for their withdrawal from use. Hence research is now focusing on the use of natural antioxidants such as vitamin E, Vitamin C and other plant phenolic substances [11] The aims of this study were to formulate a dried infant food product using sweet potato; to investigate the nutritional and rheological properties of the product and to study the effects of antioxidants (Vitamin E and C) on lipid oxidation in the product during storage…”

Section: Introductionmentioning

confidence: 99%

Nutritional and rheological properties of swet potato based infant food and its preservation using antioxidants

Nandutu¹,

Howell²

2009

African Journal of Food, Agriculture, Nutrition and Development

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Sweet potato based infant food was developed according to micro-diet database program, 2000, Down lee Systems Limited. Two sweet potato based recipes were formulated and their nutritional properties and digestibility measured using standard analytical methods. The viscosity or consistency of a baby food was critical and was determined by measuring the rheology of the product. The oscillation technique was used to determine the elastic energy stored (G') and the energy dissipated due to viscosity (G''). The effects of antioxidants on lipid oxidation of the developed products on storage were also investigated. The recipes were compared with two commercial infant food products; Heinz baby food and cerelac®. The mean ± SD for moisture, total carbohydrate, protein, crude fat, and ash per 100 g dry weight were 8 ± 0.4, 66 ± 0.2, 20.4 ± 0.1, 2.0 ± 0.1, 3.2 ± 0.8 g, respectively for recipe A, and 8.4 ± 0.6, 58 ± 1.4, 28 ± 0.4, and 3.4 ± 0.5, 2.0 ± 0.0 g, respectively for recipe B. The in vitro digestibility for recipes A, B and commercial food (cerelac®) were 69.5 ± 0.2, 67.4 ± 0.1 and 64.9 ± 1.9% respectively. The G' values of the formulated products A, B, Heinz baby food and cerelac® on heating and cooling were 564, 492, 346, 21 Pa. The rheological characteristics of the two formulations were comparable to a commercial Heinz baby food obtained from local super market. The G' and G'' values of commercial infant food product cerelac® were very low compared with the formulated product. The results indicated that nutritional characteristics of sweet potato based products were comparable to the commercial baby food, cerelac® used in Uganda. The formulated food was within the accepted consistency (< 500 Pa) after heating and cooling and hence may be a potential complementary food. The lipid oxidation for recipe A with fish was significantly reduced by using antioxidants (500 mg Vitamin C, 500 mg Vitamin E and 100 mg of Citric acid) whereas recipe B did not need any antioxidants.

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“…Animals were treated daily at dose levels of 0 (corn oil only), 75 or 450 mg/kg for 7 days. In previously reported studies, hepatocellular necrosis was seen in male rats given BHT at 500 mg/kg/day for 7 days 5 . Four rats from each group were sampled after 1, 3, 7, 9, 11, and 14 days of treatment.…”

Section: Methodsmentioning

confidence: 99%

Effect of Butylated Hydroxytoluene on Cell Population in Rat Hepatocytes.

et al. 2001

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Abstract:In order to examine the effect of 3,5-di-tert-butyl-4-hydroxytoluene (BHT) on hepatocellular population, BHT was given orally to male rats for 7 consecutive days at dose levels of 75 or 450 mg/kg/day. BHT induced hepatocellular proliferation, increase in apoptosis, and elevated immunoreactivity for transforming growth factor (TGF)-β1 during the treatment, and hepatocellular mitoinhibition following the withdrawal. The induction of mitoinhibition, apoptosis, and TGF-β1 might be adaptive changes in response to cell proliferation; thus the homeostasis of hepatocellular population was preserved. Although both the mechanism and the biological significance of mitoinhibition observed following the withdrawal of BHT, after a 7-day treatment period, were not elucidated, its mechanism seemed to be related to the elevation of TGF-β1 immunoreactivity and its biological significance might be similar to those with non-genotoxic hepatocarcinogens in chronic treatments. (J Toxicol Pathol 2001; 14: 145-150)

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Hepatic responses to the administration of high doses of BHT to the rat: Their relevance to hepatocarcinogenicity

Cited by 57 publications

References 23 publications

Effects of Induction and Inhibition of Cytochromes P450 on the Hepatotoxicity of Methapyrilene

Effects of Induction and Inhibition of Cytochromes P450 on the Hepatotoxicity of Methapyrilene

Nutritional and rheological properties of swet potato based infant food and its preservation using antioxidants

Effect of Butylated Hydroxytoluene on Cell Population in Rat Hepatocytes.

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