Ovine urinary metabolites of ethoxyquin

Kim, H. L.; Ray, A. C.; Calhoun, M.C.

doi:10.1080/15287399209531674

Cited by 11 publications

(7 citation statements)

References 13 publications

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“…Previous investigators (Skaare andSolheim 1979, ter Mulen et al 1980) deethylation as the major metabolic pathway, however these studies used GC-MS, with hydrolysis of conjugates as part of the work-up, and only the free phenol was detected. In a GC-MS study that did not use enzymatic hydrolysis, the free phenol was not detected in either rat or sheep (Kim et al 1992). In the present study the conjugates were characterized and it was determined that the 0-sulphate is the predominant conjugate in the rat and the phenol was eliminated as both the 0sulphate and 0-glucuronide in mouse.…”

Section: Discussionmentioning

confidence: 94%

“…T h e free phenol was not detected in urine from either rat or mouse. Several hydroxylated urinary metabolites of EQ have been postulated based on GC-MS data in earlier studies (Skaare and Solheim 1978, ter Mulen et al 1980, Kim et al 1992, however the position of the hydroxyl groups could not be determined based on the M S data. One conjugate of an hydroxylated metabolite (H) was characterized in the present study.…”

Section: Discussionmentioning

confidence: 97%

“…Earlier studies have identified several EQ metabolites in the rat (Skaare 1979, Skaare andSolheim 1979, ter Mulen et al 1980) and sheep (Kim et al 1992) using GC/MS techniques. One of these metabolites, 2,2,4-trimethylquinol-6-one (TQ ; figure l), was especially intriguing because of its similarity to quinoneimine intermediates, such as NAPQl (figure l), considered to be the toxic species derived from acetaminophen, paminophenol and related compounds (Monks and Lau 1988, Vermeulen et al 1992).…”

Section: Introductionmentioning

confidence: 97%

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Comparative metabolism and disposition of ethoxyquin in rat and mouse. II. Metabolism

Burka¹,

Sanders²,

Matthews³

1996

Xenobiotica

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1. The major pathways of ethoxyquin (EQ) metabolism in both the rat and mouse are O-deethylation and conjugation to endogenous substrates. 2. The two major EQ-derived metabolites excreted in rat urine were in the form of sulphate conjugates, 1,2-dihydro-6-hydroxy-2,2,4-trimethylquinoline sulphate, and 1,2,3,4-tetrahydro-3,6-dihydroxy-4-methylene-2,2-dimethylquinoline sulphate. The latter apparently arises from an intramolecular rearrangement of the 3,4-epoxide of ethoxyquin. 3. Mouse urine contained one major glucuronide, 1,2-dihydro-6-hydroxy-2,2,4-trimethylquinoline glucuronide as well as one major sulphate conjugate, 1,2-dihydro-6-hydroxy-2,2,4-trimethylquinoline sulphate. 4. EQ-derived radioactivity was excreted in rat bile, mainly as GSH conjugates, with little unchanged EQ present. Two of the biliary metabolites are glutathione conjugates of ethoxyquin 3,4-epoxide; the third appears to be a conjugate of either ethoxyquin 7,8-epoxide or 2,2,4-trimethylquinol-6-one.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 97%

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Comparative metabolism and disposition of ethoxyquin in rat and mouse. II. Metabolism

Burka¹,

Sanders²,

Matthews³

1996

Xenobiotica

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“…The biological effects of ethoxyquin include inhibition of mitochondria1 electron transport (1 87) and combined cyclooxygenasenipoxygenase inhibition (155,215). The compound undergoes oxidative metabolism and is excreted as the parent compound and both hydroxylated and dihydroxylated ethoxyquin in rat urine (122).…”

Section: Aiitioxidcliitsmentioning

confidence: 99%

Renal Papillary Necrosis—40 Years On

Bach

Thanh

1998

Toxicol Pathol

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Analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs) are well recognized as a major class of therapeutic agent that causes renal papillary necrosis (RPN). Over the last decade a broad spectrum of other therapeutic agents and many chemicals have also been rcportcd that have the potential to cause this lesion in animals and man. There is consensus that RPN is the primary lesion that can progress to cortical degeneration; and it is only at this stage that the lesion is easily diagnoscd. In the absence of sensitive and selective noninvasive biomarkers of RPN there is still no clear indication of which compound, under what circumstances, has the greatest potential to cause this lesion in man. Attempts to mimic RPN in rodents using analgesics and NSAIDs have not provided robust models of the lesion. Thus, much of the research has concentrated on those compounds that cause an acute or subacute RPN as the basis by which to study the pathogenesis of the lesion. Based on the mechanistic understanding gleaned from these model compounds it has been possible to transpose an understanding of the underlying processes to the analgesics and NSAIDs. The mechanism of RPN is still controversial. There are data that support microvascular changes and local ischemic injury as the underlying cause. Alternatively, several model papillotoxins, some analgesics, and NSAIDs target selectively for the medullary interstitial cells, which is the earliest reported aberration, after which there are a series of degenerative processes affecting other renal cell types. Many papillotoxins have the potential to undergo prostaglandin hydroperoxidase-mediated metabolic activation, specifically in the renal medullary interstitial cells. These reactive intermediates, in the presence of large quantities of polyunsaturated lipid droplets, result in localized and selective injury of the medullary interstitial cells. These highly differentiated cells do not repair, and it is generally accepted that continuing insult to these cells will result in their progressive erosion. The loss of these cells is thought to be central to the degenerative cascade that affects the cortex. There is still a need to understand better the primary mechanism and the secondary consequences of RPN so that the risk of chemical agents in use and novel molecules can be fully assessed.

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“…Studies performed on EQ metabolism in mammalian systems showed that EQ is extensively metabolized (Burka et al, 1996;Kim et al, 1992;Sanders et al, 1996;Skaare and Solheim, 1979). The major pathways of EQ metabolism in rodents are three cytochrome P450 (CYP)-mediated Odeethylation, hydroxylation, and epoxydation followed by conjugation with endogenous products that are subsequently excreted through urine, bile, or faeces (Burka et al, 1996).…”

mentioning

confidence: 99%

Hepatic Biotransformation and Metabolite Profile during a 2-Week Depuration Period in Atlantic Salmon Fed Graded Levels of the Synthetic Antioxidant, Ethoxyquin

Bohne¹,

Hamre²,

Arukwe³

2006

Toxicological Sciences

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The synthetic antioxidant ethoxyquin (EQ) is increasingly used in animal feeds and has been candidate for carcinogenicity testing. EQ has the potential for toxicological and adverse health effects for both fish and fish consumers through "carryover" processes. The toxicological aspects of EQ have not been systematically investigated. The present study was performed to investigate the hepatic metabolism, metabolite characterization, and toxicological aspects of EQ in salmon during a 2-week depuration after a 12-week feeding period with 18 mg (low), 107 mg (medium), and 1800 mg/kg feed (high). The alteration in gene expressions and catalytic activities of hepatic biotransformation enzymes were studied using real-time polymerase chain reaction with specific primer pairs and by kinetics of two identified hepatic metabolites. Analysis of EQ metabolism was performed using high performance liquid chromatography (HPLC) method and showed the detection of four compounds of which two were quantified, parent EQ and EQ dimer (EQDM). Two metabolites were identified as de-ethylated EQ (DEQ) and quinone imine, but these were not quantified. The concentration of the quantified EQ-related compounds in the liver at day 0 showed a positive linear relationship with measured dietary EQ (R2= 0.86 and 0.92 for parent EQ and EQDM, respectively). While the low-EQ-feeding group showed a time-specific increase of aryl hydrocarbon receptor (AhR) mRNA expression, the medium-dose group showed decreased AhR mRNA at depuration day 7. Expression of CYP1A1 was decreased during the depuration period. Consumption of dietary EQ produced the expression of CYP3A, glutathione S-transferase (GST), and uridine diphosphate glucuronosyl-transferase (UDPGT) mRNA during the depuration period. A similar pattern of effect was observed for both CYP3A and phase II genes and supports our previous postulation of common regulation of these enzymes by the same inducer, namely EQ metabolites. The increase of CYP3A, UDPGT, and GST gene expressions at day 7 was in accordance with the low concentration of DEQ. The low concentration of putative DEQ may induce the CYP3A with subsequent increase in the biotransformation of EQ into DEQ. The increase in UDPGT may seem to be a synchronizing mechanism required for the excretion of DEQ. The biotransformation of dietary EQ is proven by simultaneous induction of both phase I and II detoxification system in the liver of Atlantic salmon. Therefore, the apparent low concentration of putative DEQ may account for the induced phase I and II detoxifying enzymes at least during depuration. This speculated hypothesis is currently a subject for systematic investigation in our laboratory using in vitro and genomic approaches.

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Ovine urinary metabolites of ethoxyquin

Cited by 11 publications

References 13 publications

Comparative metabolism and disposition of ethoxyquin in rat and mouse. II. Metabolism

Comparative metabolism and disposition of ethoxyquin in rat and mouse. II. Metabolism

Renal Papillary Necrosis—40 Years On

Hepatic Biotransformation and Metabolite Profile during a 2-Week Depuration Period in Atlantic Salmon Fed Graded Levels of the Synthetic Antioxidant, Ethoxyquin

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