The administration of the antihistamine, methapyrilene, to man was recently banned in the U.S.A. after it was found that virtually 100% of rats receiving methapyrilene developed hepatocarcinoma. The primary objective of this proposal is to examine the in vitro metabolic pathways of the antihistamine, methapyrilene, that involve the 2-aminopyrido- and the thiophenl-substituents contained in its structure. Similar metabolic data will then be obtained for methaphenilene (in which the pyridine ring of methapyrilene has been replaced by a phenyl ring, but the thiophenl and other remaining moieties are identical) and pyribenzamine (in which the thiophene ring of methapyrilene is replaced by a phenyl ring, but the 2-aminopyrido- and other remaining moieties are identical). A comparison of these data with those obtained for methapyrilene should indicate the effects that the thiophene and/or 2-aminopyrido-moieties have on both binding and the metabolic profile, and thus evaluate the effects of the presence of these structural features on the hepatic metabolism of methapyrilene. The focus of the work will be on the in vitro liver metabolism and the metabolism will be monitored quantitatively so that the presence of bound metabolites may be detected. Since pyribenzamine is still utilized in the market place, these data will indicate whether or not any metabolic route leading to potentially toxic metabolites exists for pyribenzamine. In addition, screening of each metabolite found by the """"""""Ames"""""""" mutagenesis assay will quantitate the relative degree of mutagenicity that exists in the metabolic products formed. Both recent literature data and preliminary data presented in this proposal are discussed which support the primary hypothesis of the proposal, namely, that metabolism of the 2-aminopyrido-ring and/or the thiophenl-moiety leads to bioactivation, toxicity, mutagenicity and perhaps, carcinogenicity.
