Influence of a benzoquinolizinyl derivative on serum and hepatic alkaline phosphatase activity in the dog and rat

Leeling, Jerry L.; Hartnagel, Ralph E.; Bare, James J.; Fonseca, Emma H.; Kraus, P.; Kowalski, Robert L.

doi:10.1016/0300-483x(75)90102-x

Cited by 11 publications

(8 citation statements)

References 8 publications

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“…The phenomenon seemed to be unique to the canine species, since no similar phenomena have been reported for other species to our knowledge up to the present time. Hyperphosphatasemias without any other toxicological signs in dogs in practical toxicity studies using various compounds, at least some of them, seemed to belong to the same category with that reported in the present study for PBtreated dogs, and marked changes in ALP levels during drug treatment should not automatically be assumed to have toxicologic implications as stated by Leeling and others 17 . Therefore, the reported hyperphosphatasemia recorded in PB-treated dogs and similar phenomena due to DME inducing agents have to be dealt with separately from the toxicologically significant changes as seen in ANIT-treated dogs.…”

Section: Discussionsupporting

confidence: 52%

“…PB-induced hyperphosphatasemia has attracted, as stated in the introduction, the attention of toxicologists in connection with DME induction [2][3][4][5][17][18][19] . Litchfield and Conning confirmed inhibition of PB-induced DME induction and variation in ALP activity by cycloheximide and stated that raised plasma ALP in dogs following PB administration is derived from a drug-induced effect on the hepatic enzyme 4 .…”

Section: Discussionmentioning

confidence: 99%

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Comparison of Pathologic Features in Experimental Hyperphosphatasemic Conditions in Beagle Dogs Treated with .ALPHA.-Naphthylisothiocyanate and Phenobarbital.

et al. 2002

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Abstract:The present study was designed to clarify the pathologic features of hyperphosphatasemic conditions in association with drug metabolizing enzyme (DME) induction and cholestatic condition in dogs. Two (2) model compounds were selected; α-naphthylisothiocyanate (ANIT) and phenobarbital (PB). Groups of beagle dogs were orally given ANIT at 30 mg/kg or PB at escalating dose of 20 to 60 mg/kg for 3 weeks and subjected to in-life and postmortem examinations. Determination of hepatic DME and alkaline phosphatase (ALP) activity in liver tissue fractions as well as isoenzyme analysis of serum ALP were performed. Differences between the ANIT and PB groups were: (1) the serum enzyme profile in the ANIT group was characterized by remarkably elevated activity in leakage enzymes (ALT and AST) and ALP accompanied by a remarkable increase in plasma total bilirubin concentration and remarkable inhibition of ICG clearance, (2) the only noticeable finding in the serum enzyme profile in the PB group was remarkable elevation of ALP activity, and (3) microsomal P-450 content decreased in the ANIT group and increased in the PB group. Activities of aminopyrine demethylase and aniline hydroxylase shifted together with the change in microsomal P-450 content in the PB group, and (4) degenerative changes in the biliary system and liver cells were characteristic in the ANIT group and hyperplasia of the smooth surfaced endoplasmic reticulum was prominent in the PB group. The reported hyperphosphatasemia recorded in the PB-treated dogs has to be dealt with separately from the toxicologically significant changes seen in ANIT-treated dogs, since the source of ALP differed between the two conditions. (J Toxicol Pathol 2002; 15: 49-59)

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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Comparison of Pathologic Features in Experimental Hyperphosphatasemic Conditions in Beagle Dogs Treated with .ALPHA.-Naphthylisothiocyanate and Phenobarbital.

et al. 2002

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“…1971;Leeling et al 1975;Robertson et al 1993). These studies correlated an increase in ALP activity with increased microsomal enzyme activity and demonstrated that the source of the ALP increase was of hepatic origin in the absence of histologically detectable hepatobiliary injury.…”

Section: Alkaline Phosphatase (Alp)mentioning

confidence: 82%

“…Additionally, the ALP change reported by Robertson et al (1993) was not associated with any other changes in clinical pathology parameters. Leeling et al (1975) concluded that marked changes in ALP levels during drug treatment should not automatically be assumed to have toxicological implications.…”

Section: Alkaline Phosphatase (Alp)mentioning

confidence: 99%

Liver Hypertrophy

Elcombe²,

et al. 2012

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Preclinical toxicity studies have demonstrated that exposure of laboratory animals to liver enzyme inducers during preclinical safety assessment results in a signature of toxicological changes characterized by an increase in liver weight, hepatocellular hypertrophy, cell proliferation, and, frequently in long-term (life-time) studies, hepatocarcinogenesis. Recent advances over the last decade have revealed that for many xenobiotics, these changes may be induced through a common mechanism of action involving activation of the nuclear hormone receptors CAR, PXR, or PPARa. The generation of genetically engineered mice that express altered versions of these nuclear hormone receptors, together with other avenues of investigation, have now demonstrated that sensitivity to many of these effects is rodent-specific. These data are consistent with the available epidemiological and empirical human evidence and lend support to the scientific opinion that these changes have little relevance to man. The ESTP therefore convened an international panel of experts to debate the evidence in order to more clearly define for toxicologic pathologists what is considered adverse in the context of hepatocellular hypertrophy. The results of this workshop concluded that hepatomegaly as a consequence of hepatocellular hypertrophy without histologic or clinical pathology alterations indicative of liver toxicity was considered an adaptive and a non-adverse reaction. This conclusion should normally be reached by an integrative weight of evidence approach.

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“…The elevation of serum alkaline phospha tase (AP) has been noted in a number of experimental studies when dogs were treated with compounds that caused few if any toxi cological effects [1][2][3], Although elevated se rum AP has long been known to accompany drug-induced cholestasis in various species [4], its significance in the absence of histopathologically detectable liver damage is not clear. The interpretation of serum AP eleva tions observed in experimental studies is hindered by a general lack of information on but the organ sources of two of the AP enzymes could only be identified by indirect methods.…”

Section: Introductionmentioning

confidence: 99%

Further Characterization of Serum Alkaline Phosphatase from Male and Female Beagle Dogs

Amacher

Higgins²,

Schomaker³

et al. 1989

Enzyme

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Alkaline phosphatase (AP) from the sera of both male and female beagle dogs was partially purified and then analyzed for the presence of AP isoenzymes having intestinal or osseous characteristics as detected by bromotetramisole inhibition or wheat germ lectin agarose electrophoresis, respectively. The sera from both sexes were similar in regard to the presence of AP isoenzymes with intestinal (16 vs. 20%) or osseous (19 vs. 23%) characteristics, but serum AP from the male had a greater sialic acid content and only the male serum contained a detectable constitutive acidic (pI = 3.4) AP isoenzyme. This was similar to a serum AP isoenzyme previously found elevated in the sera of dogs afflicted with hyperadrenocorticalism or of dogs treated with certain corticosteroids.

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Influence of a benzoquinolizinyl derivative on serum and hepatic alkaline phosphatase activity in the dog and rat

Cited by 11 publications

References 8 publications

Comparison of Pathologic Features in Experimental Hyperphosphatasemic Conditions in Beagle Dogs Treated with .ALPHA.-Naphthylisothiocyanate and Phenobarbital.

Comparison of Pathologic Features in Experimental Hyperphosphatasemic Conditions in Beagle Dogs Treated with .ALPHA.-Naphthylisothiocyanate and Phenobarbital.

Liver Hypertrophy

Further Characterization of Serum Alkaline Phosphatase from Male and Female Beagle Dogs

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