Toxicological response of rats to a novel monoamine oxidase type-A inhibitor, (5R)-3-[2-((1S)-3-cyano-1-hydroxypropyl)benzothiazol-6-yl]-5- methoxymethyl-2-oxazolidinone (E2011), orally administered for 13 weeks.
(5R)-3-[2-((1S)-3-cyano-1-hydroxypropyl)benzothiazol-6-yl]-5- methoxymethyl-2-oxazolidinone (E2011) is a novel monoamine oxidase type-A (MAO-A) inhibitor. In order to assess toxicological profiles of E2011, doses of 0 (as controls), 30, 100 mg/kg of E2011 were administered to male and female Sprague-Dawley rats once a day for 13 weeks orally by gavage. No mortality or any toxic signs except salivation occurred due to E2011 treatment. Decreased body weight gain and food consumption, increases of alkaline phosphatase and increases of liver weight were the major treatment-related findings observed predominantly in the 100 mg/kg group. Histological examination revealed nuclear enlargement of hepatocytes with appearance of altered cell foci in some cases, and acinar atrophy in Harderian glands in the 100 mg/kg group. Since the histopathological findings in the liver were indicative of an ongoing carcinogenic process, glutathione S-transferase placental form (GST-P) positive hepatic foci were identified immunohistochemically and examined morphometrically. Although GST-P positive hepatic foci were detected in all groups including controls, the number and area of GST-P positive hepatic foci were significantly higher in female rats treated with 100 mg/kg than those in controls. In this paper, possible mechanisms of specific lesions in the liver and Harderian glands will be discussed.
Sato
G
G
Drug Safety & Disposition Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
Chimoto
T
T
Aoki
T
T
Hosokawa
S
S
Sumigama
S
S
Tsukidate
K
K
Sagami
F
F
D000284:Administration, Oral; D000818:Animals; D052160:Benzothiazoles; D001835:Body Weight / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D005260:Female; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000032:analysis; D006243:Harderian Gland / Q000187:drug effects / Q000473:pathology; D006403:Hematologic Tests; D007527:Isoenzymes / Q000032:analysis; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D008297:Male; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D010080:Oxazoles / Q000737:chemistry / Q000633:toxicity*; D023303:Oxazolidinones; D011230:Precancerous Conditions / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012472:Salivation / Q000187:drug effects; D013844:Thiazoles / Q000737:chemistry / Q000633:toxicity*
D052160:Benzothiazoles; C091708:E 2011; D007527:Isoenzymes; D008996:Monoamine Oxidase Inhibitors; D010080:Oxazoles; D023303:Oxazolidinones; D013844:Thiazoles; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; C496558:Gstp1 protein, rat