کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
5857551 1562131 2011 9 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Toxicological approach for elucidation of clobazam-induced hepatomegaly in male rats
موضوعات مرتبط
علوم زیستی و بیوفناوری علوم محیط زیست بهداشت، سم شناسی و جهش زایی
پیش نمایش صفحه اول مقاله
Toxicological approach for elucidation of clobazam-induced hepatomegaly in male rats
چکیده انگلیسی

Antiepileptic agents are known to cause adverse effects in human liver, including steatosis. Clobazam (CLB), a 1,5-benzodiazepine, is clinically used as an antiepileptic agent. In the previous study, 4-week treatment with CLB induced hepatomegaly in male rats. In the present study, the human risk of hepatomegaly was assessed and the causative mechanism in terms of cell proliferation and apoptosis, oxidative stress, and drug-metabolizing enzyme induction was elucidated by toxicological approach. Male SD rats were treated orally with 400 mg/kg CLB for 1, 3, 7, 14, or 28 days. The 28-day treatment was followed by 7 or 14 days of withdrawal. At the end of each treatment, the liver and plasma of each rat were examined. Liver weight increased from Day 3 of CLB treatment. This increase was mostly accompanied by hepatic centrilobular hypertrophy and proliferation of smooth endoplasmic reticulum (SER), and by an increase in microsomal proteins. Cyp2b1, Cyp3a1, Cyp3a2, and Ugt2b2 mRNA levels in the liver were upregulated as compared to the control group throughout the dosing period. On the other hand, the thiobarbituric acid reactive substance (TBARS) formulation, hepatocyte proliferation, and apoptosis, assumed to play roles in laying groundwork for effective induction of metabolizing enzymes, were increased only at the acute phase of treatment. These results suggested that CLB-induced hepatomegaly in male rats is mainly attributable to microsomal enzyme induction associated with Cyp2b1, Cyp3a1, Cyp3a2, and Ugt2b2 gene upregulation, but does not cause any toxicological concerns.

► Investigation of the process of hepatomegaly induced by clobazam in male rats. ► Oxidative stress, cell proliferation and apoptosis occurred prior to the hepatomegaly in the acute phase of treatment. ► Hepatomegaly was accompanied by Cyp2b1, Cyp3a1, Cyp3a2, and Ugt2b2 gene upregulation in the subchronic phase of treatment. ► Clobazam is unlikely to cause hepatomegaly in humans.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Regulatory Toxicology and Pharmacology - Volume 60, Issue 3, August 2011, Pages 323-331
نویسندگان
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