کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2587901 1130944 2006 10 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
The relationship among microsomal enzyme induction, liver weight, and histological change in cynomolgus monkey toxicology studies
موضوعات مرتبط
علوم زیستی و بیوفناوری علوم کشاورزی و بیولوژیک دانش تغذیه
پیش نمایش صفحه اول مقاله
The relationship among microsomal enzyme induction, liver weight, and histological change in cynomolgus monkey toxicology studies
چکیده انگلیسی

The purpose of this investigation was to examine the relationship among hepatic microsomal enzyme induction, liver weight, histological evidence of hepatic injury, and serum clinical chemistry markers of hepatic origin in the cynomolgus monkey. We report here the results from independent toxicology studies for 10 investigative drug candidates representing four therapeutic classes. Study conditions were selected to elicit target organ toxicity. We found that six of the 10 compounds altered cytochrome P450-associated activities in both male and female monkeys, two in females only, and one altered similar activities in males only. Frequently, significant treatment-related elevations in NADPH cytochrome c reductase and ethylmorphine N-demethylase were noted. When the results from all 10 studies were pooled, 14 cytochrome P450-associated activities were significantly increased and five were decreased in males compared to 15 significantly increased and three decreased in the females. Treatment-associated liver weight increases were noted in four studies. Except for hepatocellular hypertrophy in one study, no significant treatment-related microscopic changes in liver and no elevations of serum biomarkers commonly associated with liver toxicity were observed in any of the studies that demonstrated significant hepatic enzyme induction. Compared to parallel rat studies, one compound was an inducer only in monkeys and one was an inducer only in rats. Significant elevations of microsomal drug-metabolizing enzymes in the cynomolgus monkey liver are not accompanied by substantial hepatic changes except for hepatomegaly. These alterations in the hepatic drug-metabolizing enzyme system were benign based the absence of histopathological lesions and serum biomarkers of hepatobiliary toxicity.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Food and Chemical Toxicology - Volume 44, Issue 4, April 2006, Pages 528–537
نویسندگان
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