Assessment of oral toxicity and safety of pentamethylchromanol (PMCol), a potential chemopreventative agent, in rats and dogs.
2,2,5,7,8-Pentamethyl-6-chromanol (PMCol) was administered by gavage in rats for 28 days at dose levels of 0, 100, 500, and 2000mg/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 upward arrow and PT downward arrow) and hyperkeratosis of the nonglandular stomach in the 2000mg/kg/day dose group (in one or both sexes). In the 500mg/kg/day dose group, toxicity was seen to a lesser extent. In the 100mg/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 800mg/kg/day (four male dogs/dose group). PMCol treatment at 800mg/kg/day resulted in pronounced toxicity to the male dogs. Target organs of toxicity were liver and thymus. Treatment at 200mg/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 800mg/kg administered orally did not have an effect on the QT interval, blood pressures and body temperatures following dosing over a 24-h 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 100mg/kg/day and 50mg/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 100mg/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 sensitivity to nephrotoxicity, while female animals had a greater incidence of hepatoxicity and changes in hematological parameters evaluated, especially at a dose of 500mg/kg/day, which correlated to the higher plasma drug levels in female rats. It appeared that dogs were generally more sensitive than rats to oral administration of PMCol. Further examination of the potential toxic effects of PMCol in longer term studies is required prior to understanding the full risks of PMCol administration as a chemopreventative agent.
Lindeblad
Matthew
M
Toxicology Research Laboratory, Department of Pharmacology, University of Illinois at Chicago, Rm. 1306, Chicago, IL 60612, USA.
Kapetanovic
Izet M
IM
Kabirov
Kasim K
KK
Detrisac
Carol J
CJ
Dinger
Nancy
N
Mankovskaya
Irina
I
Zakharov
Alexander
A
Lyubimov
Alexander V
AV
D000284:Administration, Oral; D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage / Q000633:toxicity*; D002839:Chromans / Q000008:administration & dosage / Q000633:toxicity*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D018675:Toxicity Tests
D016588:Anticarcinogenic Agents; D002839:Chromans; C029141:2,2,5,7,8-pentamethyl-1-hydroxychroman