Toxicologic Pathology

 

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This version was published on April 1, 2008
Toxicologic Pathology, Vol. 36, No. 3, 420-427 (2008)
DOI: 10.1177/0192623308315359

Articles

Relationship between GST Yp Induction and Hepatocyte Proliferation in Rats Treated with Phase II Drug Metabolizing Enzyme Inducers

Toshihiko Makino1,2, Kayoko Ishikawa1, Isao Igarashi1, Takashi Yamoto1, Sunao Manabe1 and Hiroyuki Nakayama2

1 Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Fukuroi, Shizuoka 437-0065, Japan
2 Department of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, University of Tokyo, Tokyo 113-8657, Japan

Correspondence: Address correspondence to: Toshihiko Makino, Address: Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 717 Horikoshi, Fukuroi, Shizuoka 437-0065, Japan; e-mail:makino.toshihiko.f7{at}daiichisankyo.co.jp.

Butylated hydroxyanisole (BHA) and 1,2-bis(2-pyridyl)ethylene (2PY-e) are phase II drug metabolizing enzyme inducers which cause hepatomegaly without hepatocyte hypertrophy and induce glutathione S-transferase Yp (GST Yp, pi-class GST), which is known as a tumor marker. To evaluate the relationship between GST Yp induction and hepatocyte proliferation, male F344/DuCrj rats were treated with BHA, 2PY-e, or phenobarbital (PB) for three or seven days. All three chemicals caused increases in liver weight after three and seven days. Immunohistochemical examinations revealed that BHA and 2PY-e induced GST Yp in the hepatocytes of the periportal and centrilobular areas at three and seven days, respectively, whereas PB did not. Significant increases in the BrdU labeling indices were found in the livers of rats in each of the three-day treatment groups, but the labeling index of rat livers treated with BHA was decreased to the control level at seven days, although the high labeling indices of 2PY-e and PB persisted at seven days. Double immunostaining confirmed that BrdU-positive nuclei corresponded to GST Yp-positive hepatocytes in both BHA and 2PY-e treated rats. These results suggest that the GST Yp induction caused by BHA or 2PY-e has some kind of relationship with hepatocyte proliferation.

Key Words: Butylated hydroxyanisole • 1,2-bis(2-pyridyl)ethylene • phenobarbital • GST Yp • proliferation • liver

Abbreviations: BHA, butylated hydroxyanisole • 2PY-e, 1, 2-bis(2-pyridyl) ethylene • PB, phenobarbital • GST, glutathione S-transferase • BrdU, 5-bromo-2-deoxyuridine


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