Metabolism in vivo of dioxane: identification of p-dioxane-2-one as the major urinary metabolite

Woo, Yin-tak; Arcos, Joseph C.; Argus, Mary F.; Griffin, G. W.; Nishiyama, Kazvyoshi

doi:10.1016/0006-2952(77)90430-0

Cited by 26 publications

(16 citation statements)

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“…Values are means ±SD (n=3) differentially CYP isoforms, showing that dioxane induction is administration route dependent. In the light of pharmacokinetic studies (Woo et al 1977a(Woo et al , 1977bBraun and Young 1977), it is reasonable to suppose that the dioxane administration by gavage could cause a saturation process of its metabolism, so influencing the quantity of circulating parent compound and its metabolites and, as a consequence, the entity and profile of induction and toxicity. The treatments of rats with dioxane were also able to influence the renal but not the pulmonary expression of CYPs, evidencing an extrahepatic effect of this solvent.…”

Section: Discussionmentioning

confidence: 99%

“…Since the HEAA is the main intermediate of dioxane in vivo metabolism (De Rosa et al 1996;Woo et al 1977a;Braun and Young 1977), the peroxisomal proliferation activity of dioxane was examined by assessing the activity of a marker enzyme. Treatment of rats with 1.5% of dioxane in drinking water for 10 days did not yield any induction of the palmitoyl CoA oxidase, being 3.3±0.8 and 2.9±0.5 nmol/ min per mg protein in the control and dioxane-treated rats, respectively.…”

Section: Effect Of Chronic Dioxane Administration On Palmitoyl Coa Oxmentioning

confidence: 99%

“…In vivo investigations have identified in plasma and urine two metabolites, namely 1,4-dioxane-2-one and b-hydroxyethoxyacetic acid (HEAA), and have hypothesised an involvement of cytochrome P450 (CYP) system in this metabolism (De Rosa et al 1996;Woo et al 1977a;Braun and Young 1977), as shown in the Fig. 1.…”

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Effects of dioxane on cytochrome P450 enzymes in liver, kidney, lung and nasal mucosa of rat

et al. 2004

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The effect of acute and chronic dioxane administration on hepatic, renal, pulmonary and nasal mucosa P450 enzymes and liver toxicity were investigated in male rats. The acute treatment consisted of two doses (2 g/kg) of dioxane given for 2 days by gavage, whereas the chronic treatment consisted of 1.5% of dioxane in drinking water for 10 days. Both the acute and chronic dioxane treatments induced cytochrome P450 2B1/2- and P450 2E1-dependent microsomal monooxygenase activities (pentoxyresorufin O-depentylase and p-nitrophenol hydroxylase) in the liver, whereas in the kidney and nasal mucosa, only the 2E1 marker activities were enhanced. In addition in the liver, an induction of 2alpha-testosterone hydroxylase (associated with the constitutive and hormone-dependent P450 2C11) was also revealed, whereas the hepatic P450 4A-dependent omega-lauric acid hydroxylase was not enhanced by any dioxane treatment. These inductions were mostly confirmed by western blot analysis of liver, kidney and nasal mucosa microsomes. In the lung, no alteration of P450 activities was observed. To assess the mechanism of 2E1 induction, the hepatic, renal and nasal mucosa 2E1 mRNA levels were also examined. Following two kinds of dioxane administration, in the liver the 2E1 induction was not accompanied by a significant alteration of 2E1 mRNA levels, while both in the kidney and nasal mucosa the 2E1 mRNA increased about 2- to 3-fold, indicating an organ-specific regulation of this P450 isoform. Furthermore, dioxane was unable to alter the plasma alanine aminotransferase activity and hepatic glutathione (GSH) content, examined as an index of toxicity, when it was administered into rats with P450 2B1/2 and 2E1 preinduced by phenobarbital or fasting pretreatment. These results support the lack of or a poor formation of reactive and toxic intermediates during the biotrasformation of this solvent, even when its metabolism was enhanced by P450 inducers. The chronic administration of dioxane was also unable to induce the palmitoyl CoA oxidase, a marker of peroxisome proliferation, excluding this as a way to explain its toxicity. Thus, although the mechanism of dioxane carcinogenicity remains unclear, the present results suggest that the induction of 2E1 following a prolonged administration of dioxane might provide oxygen radical species, and thereby contribute to its organ-specific toxicity.

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Section: Discussionmentioning

confidence: 99%

Section: Effect Of Chronic Dioxane Administration On Palmitoyl Coa Oxmentioning

confidence: 99%

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Effects of dioxane on cytochrome P450 enzymes in liver, kidney, lung and nasal mucosa of rat

et al. 2004

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“…10 Rat studies with dioxane suggest that HEAA and 1,4-dioxanone may co-exist in a pH-dependent equilibrium that is heavily favored toward HEAA, 16 although 1,4-dioxanone may be favored in very acidic environments (<pH 5). 16–18 However, such a pH is not encountered even in the urine of rats with severe acidosis from high doses of DEG 9 and this compound is not observed under normal aqueous conditions in vivo. 16 …”

Section: Discussionmentioning

confidence: 99%

Characterizing concentrations of diethylene glycol and suspected metabolites in human serum, urine, and cerebrospinal fluid samples from the Panama DEG mass poisoning

Schier

Hunt

Perala

et al. 2013

Clinical Toxicology

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Context Diethylene glycol (DEG) mass poisoning is a persistent public health problem. Unfortunately, there are no human biological data on DEG and its suspected metabolites in poisoning. If present and associated with poisoning, the evidence for use of traditional therapies such as fomepizole and/or hemodialysis would be much stronger. Objective To characterize DEG and its metabolites in stored serum, urine, and cerebrospinal fluid (CSF) specimens obtained from human DEG poisoning victims enrolled in a 2006 case-control study. Methods In the 2006 study, biological samples from persons enrolled in a case-control study (42 cases with new-onset, unexplained AKI and 140 age-, sex-, and admission date-matched controls without AKI) were collected and shipped to the Centers for Disease Control and Prevention (CDC) in Atlanta for various analyses and were then frozen in storage. For this study, when sufficient volume of the original specimen remained, the following analytes were quantitatively measured in serum, urine, and CSF: DEG, 2-hydroxyethoxyacetic acid (HEAA), diglycolic acid, ethylene glycol, glycolic acid, and oxalic acid. Analytes were measured using low resolution GC/MS, descriptive statistics calculated and case results compared with controls when appropriate. Specimens were de-identified so previously collected demographic, exposure, and health data were not available. The Wilcoxon Rank Sum test (with exact p-values) and bivariable exact logistic regression were used in SAS v9.2 for data analysis. Results The following samples were analyzed: serum, 20 case, and 20 controls; urine, 11 case and 22 controls; and CSF, 11 samples from 10 cases and no controls. Diglycolic acid was detected in all case serum samples (median, 40.7 mcg/mL; range, 22.6 – 75.2) and no controls, and in all case urine samples (median, 28.7 mcg/mL; range, 14 – 118.4) and only five (23%) controls (median, 999; exact p <0.0001); and 3) urinary glycolic acid (OR = 0.057; 95% C I = 0.001–0.55). Two CSF sample results were excluded and two from the same case were averaged, yielding eight samples from eight cases. Diglycolic acid was detected in seven (88%) of case CSF samples (median, 2.03 mcg/mL; range,

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“…Initial investigations of biological dioxane transformation were performed as part of toxicological studies, which identified hydroxyethoxyacetic acid (HEAA) and 1,4-dioxane-2-one as the major metabolites in humans (55) and rats (52), respectively. Recently, the pathways of dioxane biotransformation have been studied in a number of metabolizing and cometabolizing bacteria and fungi in an attempt to understand the fate of environmentally released dioxane.…”

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confidence: 99%

Glyoxylate Metabolism Is a Key Feature of the Metabolic Degradation of 1,4-Dioxane by Pseudonocardia dioxanivorans Strain CB1190

Grostern

Sales

Zhuang

et al. 2012

Appl Environ Microbiol

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ABSTRACTThe groundwater contaminant 1,4-dioxane (dioxane) is transformed by several monooxygenase-expressing microorganisms, but only a few of these, includingPseudonocardia dioxanivoransstrain CB1190, can metabolize the compound as a sole carbon and energy source. However, nothing is yet known about the genetic basis of dioxane metabolism. In this study, we used a microarray to study differential expression of genes in strain CB1190 grown on dioxane, glycolate (a previously identified intermediate of dioxane degradation), or pyruvate. Of eight multicomponent monooxygenase gene clusters carried by the strain CB1190 genome, only the monooxygenase gene cluster located on plasmid pPSED02 was upregulated with dioxane relative to pyruvate. Plasmid-borne genes for putative aldehyde dehydrogenases, an aldehyde reductase, and an alcohol oxidoreductase were also induced during growth with dioxane. With both dioxane and glycolate, a chromosomal gene cluster encoding a putative glycolate oxidase was upregulated, as were chromosomal genes related to glyoxylate metabolism through the glyoxylate carboligase pathway. Glyoxylate carboligase activity in cell extracts from cells pregrown with dioxane and inRhodococcus jostiistrain RHA1 cells expressing the putative strain CB1190 glyoxylate carboligase gene further demonstrated the role of glyoxylate metabolism in the degradation of dioxane. Finally, we used13C-labeled dioxane amino acid isotopomer analysis to provide additional evidence that metabolites of dioxane enter central metabolism as three-carbon compounds, likely as phosphoglycerate. The routing of dioxane metabolites via the glyoxylate carboligase pathway helps to explain how dioxane is metabolized as a sole carbon and energy source for strain CB1190.

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Metabolism in vivo of dioxane: identification of p-dioxane-2-one as the major urinary metabolite

Cited by 26 publications

References 10 publications

Effects of dioxane on cytochrome P450 enzymes in liver, kidney, lung and nasal mucosa of rat

Effects of dioxane on cytochrome P450 enzymes in liver, kidney, lung and nasal mucosa of rat

Characterizing concentrations of diethylene glycol and suspected metabolites in human serum, urine, and cerebrospinal fluid samples from the Panama DEG mass poisoning

Glyoxylate Metabolism Is a Key Feature of the Metabolic Degradation of 1,4-Dioxane by Pseudonocardia dioxanivorans Strain CB1190

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