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 Similar metabolic data will then be obtained for methaphenilene (in which the pyridine ring of methapyrilene has been replaced by a phenyl ring, but the thiophenl and other remaining moieties are identical) and pyribenzamine (in which the thiophene ring of methapyrilene is replaced by a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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM031347-02
Application #
3279306
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1985-09-01
Project End
1987-06-30
Budget Start
1986-09-01
Budget End
1987-06-30
Support Year
2
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Kammerer, R C; Schmitz, D A; Lampe, M A et al. (1988) The in vivo metabolism of methapyrilene, a hepatocarcinogen, in the rat. Xenobiotica 18:869-81
Kammerer, R C; Schmitz, D A (1988) A comparative in vitro metabolic study of methaphenilene and pyribenzamine. Xenobiotica 18:1085-96
Lampe, M A; Kammerer, R C (1987) Cytochrome P-450 dependent binding of methapyrilene to DNA in vitro. Carcinogenesis 8:1525-9
Kammerer, R C; Lampe, M A (1987) In vitro metabolism of chlorpheniramine in the rabbit. Biochem Pharmacol 36:3445-52
Kammerer, R C; Kloc, K; Lampe, M A et al. (1987) Oxidation of the pyridine ring: a major pathway of metabolism for the rat hepatocarcinogen, methapyrilene. Proc West Pharmacol Soc 30:79-83
Kammerer, R C; Schmitz, D A (1987) Species differences in the in vitro metabolism of methapyrilene. Xenobiotica 17:1121-30
Lampe, M A; Kammerer, R C (1987) The effect of chronic methapyrilene treatment on methapyrilene metabolism in vitro. Carcinogenesis 8:221-6
Kammerer, R C; Schmitz, D A (1986) Metabolism of methapyrilene by rat-liver homogenate. Xenobiotica 16:671-80