Assessment of oral toxicity and safety of pentamethylchromanol (PMCol), a potential chemopreventative agent, in rats and dogs

Abstract

2,2,5,7, was administered by gavage in rats for 28 days at dose levels of 0, 100, 500, and 2000 mg/kg/day. PMCol administration induced decreases in body weight gains and food consumption, hepatotoxicity (increased TBILI, ALB, ALT, TP; increased relative liver weights; increased T4 and TSH), nephrotoxicity (increased BUN and BUN/CREAT, histopathology lesions), effect on lipid metabolism (increased CHOL), anemia, increase in WBC counts (total and differential), coagulation (FBGN↑and PT↓) and hyperkeratosis of the nonglandular stomach in the 2000 mg/kg/day dose group (in one or both sexes). In the 500 mg/kg/ day dose group, toxicity was seen to a lesser extent. In the 100 mg/kg/day dose group, only increased CHOL (females) was observed. To assess the toxicity of PMCol in male dogs it was administered orally by capsule administration for 28 days at dose levels of 0, 50, 200 and 800 mg/ kg/day (4 male dogs/dose group). PMCol treatment at 800 mg/kg/day resulted in pronounced toxicity to the male dogs. Target organs of toxicity were liver and thymus. Treatment at 200 mg/ kg/day resulted in toxicity consistent with slight adverse effect on the liver only. The results of the safety pharmacology study indicate that doses of 0, 50, 200 and 800 mg/kg administered orally did not have an effect on the QT interval, blood pressures and body temperatures following dosing over a 24-hour recording period. Under the conditions of this study, the no-observed-adverse effect level (NOAEL) for daily oral administration of PMCol by gavage for 28 days to male rats was 100 mg/kg/day and 50 mg/kg in male dogs. In female rats, the NOAEL was not established due to statistically significant and biologically meaningful increases in CHOL level seen in the 100 mg/kg/day dose group. The results of these studies indicated that administration of PMCol at higher dose levels resulted in severe toxicity in dogs and moderate toxicity in rats, however, administration at lower levels is considered to be less likely to result in toxicity following 28 days of exposure. Sex-related differences were seen in rats. Male rats appeared to have greater Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptToxicology. Author manuscript; available in PMC 2011 June 29. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript sensitivity to nephrotoxicity, while female animals had a greater incidence of hepatoxicity and changes in hematological parameters evaluated, especially at a dose of 500 mg/kg/day, which correlated to the higher plasma drug levels in female rats. I...

Toxicogenomics and Metabolomics of Pentamethylchromanol (PMCol)-Induced Hepatotoxicity

“…Rats were administered vehicle or PMCol by once daily oral gavage at a volume of 10 ml/kg/day and at concentrations of 0, 200, and 2000 mg/kg/day. Selection of these doses was based on the results of the previous toxicity study in rats (Lindeblad et al, 2010a), which indicated that the two doses, 200 and 2000 mg/kg, would cause adverse effects in the target tissues in a dose-dependent manner, optimizing the likelihood of identification of an early marker for hepatotoxicity and nephrotoxicity. The vehicle and high-dose groups were euthanized on day 8 (n ¼ 6 rats/group).…”

“…The toxicity of PMCol has been studied in both rats and dogs after 28 days of oral dose administration as part of a preclinical development program to advance PMCol as a cancer chemopreventive agent (Lindeblad et al, 2010a(Lindeblad et al, , 2010b. These studies demonstrated that daily administration of the drug candidate resulted in pronounced toxicity in both species.…”

Antidepressant-like and toxicological effects of a standardized aqueous extract of Chrysactinia mexicana A. Gray (Asteraceae) in mice

“…Changes in the body weight were daily monitored during the entire study. (Lindeblad et al, 2010;OECD, 2008). At the end of the treatments, mice were euthanized placing them in a carbon dioxide camera, then mice were beheaded and blood samples were obtained for biochemical analysis, kidney, spleen and liver were obtained for histological analysis.…”

Extending the Statistical Analysis and Graphical Presentation of Toxicity Test Results Using Standardized Effect Sizes

“…The table draws attention to the magnitude of the response for those biomarkers that are most altered. Lindeblad et al 2010). In this case, the means and SDs are not shown as it is assumed that these will be given in accompanying tables as is usual at present.…”

“…The box plot shows more clearly the increased variation as the dose group increases: evidence of toxicity. The authors TABLE 2.-SESs for 34 biomarkers and 3 dose levels (100, 500, and 2,000 mg/kg/day of pentamethylchromanol administered to rats and sorted by the top dose level (Lindeblad et al 2010 Table 1 shown graphically (Matsuo et al 2012). Note that the axes have been exchanged in order to accommodate the biomarker labels, and 23 points have been omitted, as in the table.…”