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Immunohistochemical properties of dipyrone-induced cytochromes P450 in rats

Departments of Pharmacology and Toxicology, University of Oulu

M. Pasanen

Departments of Pharmacology and Toxicology, University of Oulu

H. Sigusch

Departments of Pharmacology and Toxicology, University of Oulu

F. Stenbäck

Department of Pathology, University of Oulu, SF-90220 Oulu, Finland

S-S. Park

Laboratory of Molecular Carcinogenesis, National Cancer Institute, Bethesda, Maryland, USA

HV Gelboin

Laboratory of Molecular Carcinogenesis, National Cancer Institute, Bethesda, Maryland, USA

O. Pelkonen

Departments of Pharmacology and Toxicology, University of Oulu

1 Rat hepatic cytochrome P450s induced by dipyrone were studied enzymatically, immunochemically and immunohistochemically.

2 Dipyrone administered to male Wistar rats increased pentoxyresorufin O-depentylation (PROD), ethoxyresor ufin O-deethylation (EROD) and 7-ethoxycoumarin O- deethylation (ECOD) activities up to 44-, 1.9-, and 2.6-fold, respectively. Aryl hydrocarbon hydroxylase (AHH) activ ity was not affected.

3 Immunoinhibition with the monoclonal antibody (Mab) 2-66-3 (to CYP2B1/2) markedly decreased PROD and EROD activities, but not AHH activity. The Mab 1-7-1 (to CYP1A1/2) was without effect.

4 Histochemically, the Mab 2-66-3 gave a strong and uniform staining in livers from dipyrone-treated rats, whereas the Mab 1-7-1 gave a positive reaction in a narrow perivenous strip.

5 The induction pattern as well as inhibition by the Mabs convincingly demonstrate the predominant production of CYP2B1/2 in the induction spectrum of dipyrone. The increase in enzyme activities other than PROD may be due to the overlapping substrate specificity of CYP2B1/2 enzymes. The immunohistochemical analysis also indi cated the participation of CYP1A1/2.

Key Words: dipyrone • aminopyrine • CYP2B1/2 • drug metabolism • immunohistochemistry

Human & Experimental Toxicology, Vol. 15, No. 1, 45-50 (1996)
DOI: 10.1177/096032719601500108


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