Effect of modulators of glutathione synthesis on the hepatotoxicity of 2-methylfuran

doi:10.1016/0006-2952(91)90102-B

Biochemical Pharmacology

Volume 41, Issue 9, 1 May 1991, Pages 1311-1318

https://doi.org/10.1016/0006-2952(91)90102-B Get rights and content

Abstract

Treatment of male Sprague-Dawley rats with buthionine sulfoximine (BSO), prior to administration of carbon-14(¹⁴C)-labelled 2-methylfuran (2MF) caused a marked decrease in the covalent binding of ¹⁴C-labelled 2MF metabolites to both DNA and protein, although there was no apparent change in the distribution of the labelled parent 2MF. BSO pretreatment also protected against hepatotoxicity of 2MF, as indicated by lower serum glutamic pyruvic transaminase (GPT) levels. Pretreatment with BSO offered protection only if administered 1.5 hr before 2MF dosage. Administration of 2MF, 4 and 6 hr after BSO resulted in manifestation of the hepatotoxicity of 2MF. Prior treatment with diethylmaleate (DEM), increased covalent binding of [¹⁴C]2MF to liver proteins and also elevated serum GPT levels. Thus, depletion of tissue glutathione (GSH) by two different chemicals acting by different mechanisms produced opposite effects on the covalent binding and toxicity of 2MF. Pretreatment with L-2-oxothiazolidine-4-carboxylate (OTZ), a promoter of GSH biosynthesis, increased the hepatic covalent binding of [¹⁴C]2MF and potentiated hepatotoxicity. However, administration of OTZ and BSO prior to an i.p. dose of 100 mg/kg of 2MF, decreased the hepatic covalent binding of [ ¹⁴C]2MF and decreased the hepatotoxicity. The marked instability of the GSH conjugate of the reactive metabolite of 2MF may account for the potentiation of hepatotoxicity of 2MF by OTZ. A single s.c. dose of BSO, caused a transient increase in plasma cystine levels concurrent with the depletion of liver GSH. Administration of 2MF, 1.5 hr after BSO, significantly decreased plasma cystine levels as compared to control animals that received vehicle alone. Pretreatment with BSO also resulted in increased excretion of urinary metabolites in 2MF treated animals as compared to animals receiving 2MF alone. Thus, BSO probably protects against hepatoxicity of 2MF by indirectly causing more detoxification of the reactive metabolite of 2MF, as it does not alter the distribution of unmetabolized 2MF and does not have any apparent effect on the microsomal mixed-function oxidase which mediates the activation of 2MF. The enhanced detoxification of 2MF in BSO treated animals appears independent of the depleted GSH levels; it may result from increased availability of a better alternative nucleophile (i.e. cysteine), capable of conjugating with acetyl acrolein. Acetyl acrolein (AA) appears to be the principal reactive metabolite of 2MF which binds covalently to tissues. Previous in vitro studies have shown that cysteine is a better trapping agent of AA than GSH or N-acetyl cysteine.

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Cited by (20)

Comparative genomic analysis of Fischer F344 rat livers exposed for 90 days to 3-methylfuran or its parental compound furan
2024, Food and Chemical Toxicology
Furan is a naturally forming compound found in heat-processed foods such as coffee, canned meats, and jarred baby food. It is concurrently found with analogues including 2-methylfuran (2-MF) and 3-methylfuran (3-MF), and toxicity studies demonstrate all are potent liver toxins. Toxicity studies found 3-MF is more toxic than either furan, or 2-MF. The present analysis assesses the transcriptional response in liver samples taken from male Fischer (F344) rats exposed to furan or 3-MF from 0 to 2.0 and 0–1.0 mg/kg bw/day, respectively, for 90 days. Transcriptional analyses found decreased liver function and fatty acid metabolism are common responses to both furan and 3-MF exposure. Furan liver injury promotes a ductular reaction through Hippo and TGFB signalling, which combined with increased immune response results in ameliorating perturbed bile acid homeostasis in treated rats. Failure to activate these pathways in 3-MF exposed rats and decreased p53 activity leads to cholestasis, and increased toxicity. Finally, BMD analysis indicate many of the most sensitive pathways affected by furan and 3-MF exposure relate to metabolism - malate dehydrogenase and glucose metabolism with BMDLs of 0.03 and 0.01 mg/kg bw/day for furan and 3-MF exposure, respectively, which agrees with BMDLs previously reported for apical and microarray data.
A 90-day subchronic gavage toxicity study in Fischer 344 rats with 3-methylfuran
2018, Food and Chemical Toxicology
Citation Excerpt :
These data agree with the data collected by the World Health Organization (WHO, 2011). Until recently, little attention had been paid to the effects and presence of methylfurans in foods until 2-methylfuran and 3-methylfuran were identified to be potent hepatotoxins (Wiley et al., 1984; Ravindranath et al., 1984; Ravindranath and Boyd, 1991). Little toxicological information was available for 3-methylfuran and in most of the available studies, the route of administration was by inhalation (Haschek et al., 1983;1984; Morse et al., 1984; Gammal et al., 1984) or intraperitoneal injection.
A 90-day gavage study was conducted with 0.0, 0.02, 0.075, 0.25, 1.0 and 4.0 mg/kg bw/day dose groups of 3-methylfuran to identify a no-observed adverse effect level for hepatotoxicity and to characterize non-neoplastic effects including changes in gross anatomy, histopathology, clinical biochemistry and hematology. There were significant changes in the serum clinical biochemistry markers related to liver injury where males were more affected than the females for most parameters analysed. The serum liver injury marker γ−glutamyltransferase, alanine and aspartate aminotransferases were significantly increased in males in the 4.0 mg/kg dose group. Alkaline phosphatase was increased in females and males. There were increases in both gross and histological lesions in the liver of both sexes in addition to statistical differences in female liver weights at the 4.0 mg/kg bw/day dose. Significant increases in spleen weights were found in both genders. This was accompanied by a dose–dependent atrophy of both B- and T-cell regions in which the males were more affected. There were no significant changes in male kidney weights but there was microscopically decreased protein in the proximal tubules and crowding of their nuclei in the 4.0 mg/kg bw/day dose group. There were also significant changes in the kidney serum biomarkers including various electrolytes, blood urea nitrogen, creatinine and uric acid. A small, but significant increase in female kidney weights was observed and which increase was accompanied by changes in electrolytes, kidney specific markers and a dose-dependent increase in mineralization. In both genders, amylase decreased whereas lipase increased but these were not accompanied by any histological changes in the pancreas.
Histopathological changes in the liver were observed consistently in male and female rats in the 0.25 mg/kg dose group and higher. Hence, a lowest observed adverse effect level (LOAEL) of 0.25 mg/kg bw/d and a no observed adverse effect level (NOAEL) of 0.075 mg/kg bw/day are proposed for 3-methylfuran-induced hepatic lesions in this study. Benchmark dose modelling based on a BMR of 10% change in lesion incidence, generated BMDLs₁₀ of 0.08 mg/kg bw/day in male rats and 0.05–0.17 mg/kg bw/day in female rats for increased incidence of liver lesions.
Modulation of hepatocyte thiol content by medium composition: Implications for toxicity studies
2002, Toxicology in Vitro
Toxicity of compounds requiring glutathione for detoxification, thiol content and synthesis were determined in 24-h rat hepatocytes cultured in medium containing different concentrations of the sulphur amino acids. Glutathione synthesis was determined following prior depletion of glutathione with diethylmaleate. L-15 medium, which has high levels of cysteine and methionine (1 mm of each), provided some protection against dichloroacetone, dibromopropanol and dichloropropanol toxicity, and had a small effect on increasing glutathione content and synthesis, relative to Williams' medium E (WE) which has low levels (less than 0.5 mm) of both amino acids. However, WE containing N-acetylcysteine (NAC) (1 mm final cysteine concentration), with or without methionine (final concentration 1 mm), was a better cytoprotectant medium than L-15, markedly reducing toxicity of all three compounds, and rapidly (within 1.5 h) increasing cellular glutathione content. WE supplemented with methionine alone stimulated glutathione synthesis after an initial lag phase, and protected cultures against dichloropropanol, but not dibromopropanol or dichloroacetone, both of which are highly reactive in these cultures. There was a clear association between glutathione content at early time points in culture and toxicity observed at later time points, and overall these results indicate that differences in culture medium composition can alter intracellular glutathione content and xenobiotic toxicity.
Activity and distribution of the cysteine prodrug activating enzyme, 5-oxo-L-prolinase, in human normal and tumor tissues
1997, Cancer Letters
5-Oxo-l-prolinase (OPase), a key enzyme of the γ-glutamyl cycle, has the ability to metabolize l-2-oxothiazolidine-4-carboxylic acid (OTC) to cysteine, and thereby increase intracellular glutathione (GSH) levels. This strategy of GSH elevation can be potentially exploited to reduce normal tissue toxicity of anticancer agents, provided that sufficient differences exist in OPase levels between normal and malignant tissues. In this study, therefore, we quantitated OPase activity in primary specimens of matched and unmatched human normal and tumor (lung, breast, kidney, colon and ovary) tissues using a newly developed non-radioactive OPase assay, based on the production of cysteine from OTC. The rank order of OPase activity in extracts of 24 normal tissues examined was kidney>lung, breast and colon>ovary. OPase activity was present in all 37 tumor samples, but at variable levels. Tumor OPase levels were generally equivalent to those in their normal tissue counterparts, with the notable exception of Wilms' tumors, which had markedly lower levels than normal kidney (P<0.02). However, when 14 matched tumor and adjacent normal tissues were compared, OPase levels were significantly higher in normal specimens than tumors for individual patients (P<0.005). These higher normal tissue/tumor OPase ratios suggest that OTC may be useful in decreasing normal tissue toxicity, at least, for some tissues during cancer therapy.
Effects of culture duration, cytochrome p-450 inhibition and glutathione depletion on toxicity of diverse xenobiotics
1996, Toxicology in Vitro
The toxicity of six compounds was investigated in rat hepatocyte cultures: 3-hr cultures were exposed to toxin between 3 and 24 hr after plating and 24-hr cultures between 24 and 48 hr after plating. The toxicities of sodium dodecyl sulfate (SDS), allyl alcohol and 8-methoxypsoralen (8-MOP) were similar in 3- and 24-hr cultures, whereas precocene II, 1,3-dichloro-2-propanol (DC2P) and coumarin were all less toxic in 24-hr cultures than in 3-hr cultures. Pretreatment of cultures with the cytochrome P-450 inhibitor 1-aminobenzotriazole abolished the toxicities of coumarin and DC2P and decreased the toxicity of precocene II in both 3- and 24-hr cultures. In addition, the toxicity of precocene II appeared to correlate with the activity of the high-affinity form of 7-methoxycoumarin O-demethylase. Pretreatment of cultures with diethyl maleate (DEM) or buthionine sulfoximine (BSO) increased the toxicity of allyl alcohol, precocene II and DC2P, but not SDS. DEM enhanced the toxicity of 8-MOP in 3-hr cultures and BSO enhanced the toxicity of coumarin in 24-hr cultures. It was also demonstrated that the onset of DC2P toxicity was observed earlier in BSO-treated cultures than in DEM-treated cultures. For the compounds tested, culture age seems less important in determining toxicity than choice of glutathione-depleting agent.
Scientific Opinion on Flavouring Group Evaluation 13 Revision 3 (FGE.13Rev3): furfuryl and furan derivatives with and without additional side-chain substituents and heteroatoms from chemical group 14
2021, EFSA Journal

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Biochemical Pharmacology

Abstract

References (25)

2-Methylfuran toxicity in rats—role of metabolic activation in vivo

Toxicol Appl Pharmacol

Metabolic activation of 2-methylfuran by rat microsomal systems

Toxicol Appl Pharmacol

Protective role of endogenous pulmonary glutathione and other sulphydryl compounds against lung damage by alkylating agents; investigations with 4-ipomeanol in the rat

Biochem Pharmacol

Alteration of precocene II—induced hepatotoxicity by modulation of hepatic glutathione levels

Chem Biol Interact

The role of glutathione turnover in the apparent renal secretion of cystine

J Biol Chem

The effects of buthionine sulfoximine (BSO) on glutathione depletion and xenobiotic biotransformation

Biochem Pharmacol

The reaction of cysteine with α,β-unsaturated aldehydes

Tetrahedron

Dechlorination of l-phenylalanine mustard by sensitive and resistant tumor cells and its relationship to intracellular glutathione content

Biochem Pharmacol

Reactive metabolites from the bioactivation of toxic methyl furans

Science

Effects of cysteine pro-drugs on acetaminophen-induced hepatotoxicity

J Pharmacol Exp Ther

Synthesis of 2-([¹⁴C]methyl)furan and 4-oxo[5-¹⁴C]-2-pentenal

J Labelled Compd Radiopharm

Radiosensitization and chemosensitization by diethylmaleate

Cited by (20)

Comparative genomic analysis of Fischer F344 rat livers exposed for 90 days to 3-methylfuran or its parental compound furan

A 90-day subchronic gavage toxicity study in Fischer 344 rats with 3-methylfuran

Modulation of hepatocyte thiol content by medium composition: Implications for toxicity studies

Activity and distribution of the cysteine prodrug activating enzyme, 5-oxo-L-prolinase, in human normal and tumor tissues

Effects of culture duration, cytochrome p-450 inhibition and glutathione depletion on toxicity of diverse xenobiotics

Scientific Opinion on Flavouring Group Evaluation 13 Revision 3 (FGE.13Rev3): furfuryl and furan derivatives with and without additional side-chain substituents and heteroatoms from chemical group 14

Effect of modulators of glutathione synthesis on the hepatotoxicity of 2-methylfuran

Abstract

Toxicol Appl Pharmacol

Toxicol Appl Pharmacol

Biochem Pharmacol

Chem Biol Interact

J Biol Chem

Biochem Pharmacol

Tetrahedron

Biochem Pharmacol

Reactive metabolites from the bioactivation of toxic methyl furans

Science

Effects of cysteine pro-drugs on acetaminophen-induced hepatotoxicity

J Pharmacol Exp Ther

Synthesis of 2-([14C]methyl)furan and 4-oxo[5-14C]-2-pentenal

J Labelled Compd Radiopharm

Radiosensitization and chemosensitization by diethylmaleate

Synthesis of 2-([¹⁴C]methyl)furan and 4-oxo[5-¹⁴C]-2-pentenal