Early stages of chemically induced liver carcinogenesis by oral administration of the antihistaminic methapyrilene hydrochloride.

The antihistaminic drug methapyrilene hydrochloride, which induces liver tumors in rats, was administrated orally to female Wistar rats. The animals were killed after 21, 38, 77, 119, 181, and 196 days. The activities of adenosine-5-triphosphatase (ATPase) and gamma-glutamyltranspeptidase (gamma-GT) in the liver were investigated histochemically. At 21 days, a homogeneous decrease of ATPase activity as well as a slight increase of gamma-GT activity was found in the periportal zone. Additionally, after 38 days hepatocellular foci with reappearance of gamma-GT occurred mainly in the periportal zone. After 119 days, foci with increased gamma-GT activity as well as a significant reduction of ATPase activity could be observed predominantly in the periportal region. The size and number of these putative preneoplastic foci were increased according to the time of administration of methapyrilene hydrochloride. After 181 days of methapyrilene hydrochloride treatment three of five animals developed hyperplastic nodules with corresponding alterations of enzyme activities. Methapyrilene hydrochloride-a carcinogen with an unknown mechanism of reaction-produces preneoplastic changes that are analogous to the well known preneoplastic lesions in the liver observed after administration of other carcinogenic agents.