title: Toxicological approach for elucidation of clobazam-induced hepatomegaly in male rats.
abstract: 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.
authors.affiliation: Safety Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., Konohanaku, Osaka, Japan. izuru-miyawaki@ds-pharma.co.jp
authors.forename: Izuru
authors.initials: I
authors.lastname: Miyawaki
authors.forename: Izumi
authors.initials: I
authors.lastname: Matsumoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Horie
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inada
authors.forename: Juki
authors.initials: J
authors.lastname: Kimura
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Funabashi
authors.forename: Takaki
authors.initials: T
authors.lastname: Seki
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D001569:Benzodiazepines / Q000633:toxicity*; D049109:Cell Proliferation / Q000187:drug effects; D000078306:Clobazam; D019362:Cytochrome P-450 CYP2B1 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006529:Hepatomegaly / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008658:Inactivation, Metabolic / Q000235:genetics*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
chemical_list: D000927:Anticonvulsants; D017392:Thiobarbituric Acid Reactive Substances; D001569:Benzodiazepines; D000078306:Clobazam; D001189:Aryl Hydrocarbon Hydroxylases; D019362:Cytochrome P-450 CYP2B1