Determination of 4-methylpyrazol in serum with mass fragmentography

Björkhem, Ingemar; Blomstrand, Rolf; Lantto, Olle; Svensson, Lennart

doi:10.1016/0006-2944(75)90122-2

Cited by 18 publications

(8 citation statements)

References 5 publications

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“…We have found that dietary triglyceride significantly reduces hepatic 7␣-hydroxylase expression in rats and hamsters consuming a very low fat diet. 2 In the rat, suppression of hepatic 7␣-hydroxylase activity by dietary triglyceride was previously reported (53). Moreover, oleic acid was shown to reduce bile salt synthesis and secretion in isolated perfused rat liver (54).…”

Section: Discussionmentioning

confidence: 95%

Feedback Regulation of Hepatic 7α-Hydroxylase Expression by Bile Salts in the Hamster

Spady

Cuthbert

Willard

et al. 1996

Journal of Biological Chemistry

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Hepatic 7␣-hydroxylase activity appears to be regulated at the transcriptional level by the quantity of bile salts fluxing through the enterohepatic circulation. Whether bile salts directly suppress 7␣-hydroxylase expression at the level of the hepatocyte or do so indirectly by promoting the release or absorption of an intestinal factor has not been resolved. We have investigated the ability of primary bile salts to suppress hepatic 7␣-hydroxylase expression in bile-diverted hamsters. Biliary diversion was accompanied by derepression of both hepatic 7␣-hydroxylase activity (4 -5-fold) and bile salt secretion (ϳ3-fold). Derepression of hepatic 7␣-hydroxylase expression could be prevented by several interventions that increase the availability of bile salts within the hepatocyte including 1) overexpression of an exogenous 7␣-hydroxylase gene by adenovirus-mediated gene transfer, 2) obstruction of the common bile duct, and 3) intravenous infusions of taurocholate. In contrast, none of these interventions prevented derepression of hepatic cholesterol synthesis or significantly down-regulated hepatic low density lipoprotein receptor expression over the relatively short time course (24 h) of these studies. Together, these data indicate that primary bile salts contribute to the regulation of bile salt synthesis through feedback repression of 7␣-hydroxylase expression at the level of the hepatocyte.Conversion of cholesterol to bile salts is the principal regulated pathway whereby cholesterol is eliminated from the body. The first and rate-limiting step in this pathway is catalyzed by hepatic cholesterol 7␣-hydroxylase (1). Hepatic 7␣-hydroxylase activity appears to be regulated at the transcriptional level by the quantity of bile salts fluxing through the enterohepatic circulation (2, 3). Thus, interventions that accelerate bile salt loss from the enterohepatic circulation (thereby reducing bile salt pool size) lead to derepression of hepatic 7␣-hydroxylase expression and enhanced bile salt synthesis. Conversely, expansion of the enterohepatic pool of bile salts leads to suppression of 7␣-hydroxylase activity and reduced rates of bile salt formation.How bile salts fluxing through the enterohepatic circulation regulate the expression of hepatic 7␣-hydroxylase remains unclear. In the bile-diverted rat, depletion of the enterohepatic pool of bile salts leads to derepression of hepatic 7␣-hydroxylase activity and an increase in the rate of bile salt synthesis, effects that can be prevented by the intraduodenal administration of bile salts (4, 5). The conventional interpretation of these experiments is that the flux of bile salts through the hepatocyte (or, more likely, the concentration of bile salts within the hepatocyte) is being sensed, resulting in feedback repression of the rate-limiting enzyme in the bile salt biosynthetic pathway. However, early studies using hepatocyte suspensions or cultures failed to demonstrate any direct regulatory effect of exogenous bile salts on the secretion of bile salts into the media (6, ...

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Section: Discussionmentioning

confidence: 95%

Feedback Regulation of Hepatic 7α-Hydroxylase Expression by Bile Salts in the Hamster

Spady

Cuthbert

Willard

et al. 1996

Journal of Biological Chemistry

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“…4-MP in plasma was determined by a mass fragmentographic assay basically identical to that described (14) aminopyrine N-demethylase, and p-nitroanisol O-demethylase was determined (18).…”

Section: -Hydroxymethyl[6-2h2]pyrazole (4-oh-[6-2h2]mp) Wasmentioning

confidence: 99%

“…All other reagents were of the highest available purity. Details of the synthesis and purification of 4-methyl [6-2H3,]pyrazole have been given (14). 4-Methyl-['5N2]pyrazole was synthesized from 2-methyl-1,1,3,3-tetraethoxypropane and [15N2]hydrazine sulfate by a method described for the synthesis of 4-MP (15).…”

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confidence: 99%

Pyrazoles as inhibitors of alcohol oxidation and as important tools in alcohol research: An approach to therapy against methanol poisoning

Blomstrand

Östling-Wintzell

Löf

et al. 1979

Proc. Natl. Acad. Sci. U.S.A.

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ABSTRACT4-Methylpyrazole, in a dose producing inhibition of alcohol dehydrogenase (alcohol:NAD+ oxidoreductase, EC 1.1.1.1), was given alone or together with ethanol (10%) as sole drinking fluid to growing rats for up to 38 weeks. Their weight curves remained normal. Electron microscopy of liver, kidney, and heart revealed no changes related to treatment. Hematologic analysis showed normal values for blood and bone marrow. Several clinical chemical parameters showed no impairment of liver or kidney function, except for an enhancement of the microsomal drug-metabolizing activity after concurrent administration of 4-methylpyrazole and ethanol. A study on rats receiving 4-methylpyrazole and ethanol indicated a mutual interaction of the two compounds or the metabolites, leading to increased concentration in the blood of the compounds and reduced formation of 4-hydroxymethylpyrazole, the primary metabolite of 4-methylpyrazole. In monkeys, elimination of 4-methylpyrazole followed a linear course. 4-Hydroxymethylpyrazole accumulated to a level of at most 10% of that of 4-methylpyrazole. Concurrent administration of methanol inhibited the elimination of 4-methylpyrazole about 25%, and 4-methylpyrazole produced a profound inhibition of the oxidation of methanol. 4-Methylpyrazole, at a level in the plasma of more than 10 ,iM, prevented accumulation of the toxic metabolite formic acid in methanol-poisoned monkeys, and repeated injections of 4-methylpyrazole abolished methanol toxicity in monkeys receiving lethal doses of methanol. The present investigation indicates that 4-methylpyrazole, with its low toxicity and strong inhibition of alcohol oxidation, is a valuable tool for experimental studies of alcohol metabolism and its effects. It illustrates the usefulness of the monkey as a model to study 4-methylpyrazole activity and toxicity in light of its possible use for treating methanol poisoning in human beings.

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“…[1][2][3][4] There is a need for a critically evaluated reference method for cortisol to provide an accuracy base to which routine methods can be traceable. Reference methods for cortisol generally apply isotope dilution (ID)-gas chromatography-mass spectrometry (GC-MS) after the transformation of cortisol into its dimethoxime tri(trimethylsilyl) ether (MOX-TMS) or heptafluorobutyric anhydride (HFBA) derivatives.…”

Section: Introductionmentioning

confidence: 99%

Development of a Candidate Reference Measurement Procedure for the Analysis of Cortisol in Human Serum Samples by Isotope Dilution-Gas Chromatography-Mass Spectrometry

Kawaguchi

Takatsu

2009

ANAL. SCI.

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A candidate reference measurement procedure involving isotope dilution coupled with gas chromatography-mass spectrometry (GC-MS) has been developed and critically evaluated. An isotopically labeled internal standard, cortisol-d2, was added to a serum sample. After equilibration, solid-phase extractions (SPE) for sample preparation and derivatization with heptafluorobutyric anhydride (HFBA) were performed for GC-MS analysis. The limit of detection (LOD) and the limit of quantification (LOQ) were 5 and 20 ng g -1 , respectively. The recovery of the added cortisol ranged from 99.8 to 101.0%. Excellent precision was obtained with a within-day variation (RSD) of 0.7% for GC-MS analysis. The accuracy of the measurement was evaluated by comparing of results of this reference measurement procedure on lyophilized human serum reference materials for cortisol (European Reference Materials (ERM)-DA 192) as Certified Reference Materials (CRMs). The results of this method for total cortisol agreed with the certified values within some uncertainty. This method, which demonstrates simply, easy, good accuracy, high precision, and is free from interferences from structural analogues, qualifies as a reference measurement procedure.

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Determination of 4-methylpyrazol in serum with mass fragmentography

Cited by 18 publications

References 5 publications

Feedback Regulation of Hepatic 7α-Hydroxylase Expression by Bile Salts in the Hamster

Feedback Regulation of Hepatic 7α-Hydroxylase Expression by Bile Salts in the Hamster

Pyrazoles as inhibitors of alcohol oxidation and as important tools in alcohol research: An approach to therapy against methanol poisoning

Development of a Candidate Reference Measurement Procedure for the Analysis of Cortisol in Human Serum Samples by Isotope Dilution-Gas Chromatography-Mass Spectrometry

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