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.
Nelson DR et al. The P450 superfamily: update on new sequences, gene mapping, early trivial names of enzymes, and nomenclature. DNA Cell Biol1993; 12: 1-51.
2.
Schoene B. et al. Determination of drug metabolizing enzymes in needle biopsies of human liver. Eur J Clin Pharmacol1972; 4: 65 -73.
3.
Ackermann E. et al. Aminophenazonhalbwertszeit bei Patienten mit chronischem Leberparenchymschaden. Zeitsch Gesamte Innere Med1972; 27: 849-853.
4.
Guengerich FP et al. Purification and characterization of liver microsomal cytochromes P-450: electrophoretic, spectral, catalytic, and immunochemical properties and inducibility of eight isozymes isolated from rats treated with phenobarbital or β-naphthoflavone. Biochemistry1982; 21: 6019-6030.
Powis G., Talcott RE, Schenkman JBKinetic and spectral evidence for multiple species of cytochrome P-450 in liver microsomes. In Microsomes and Drug Oxidations. Ullrich V et al. (eds). Oxford: Pergamon Press, 1977.
7.
Halberkann J. , Fretwurst FJStoffwechselprodukte des Pyramidon und verwandter Verbindungen beim Menschen. Hoppe-Seyler's Zeitsch Physiol Chem1950; 285: 97-127.
8.
Volz M., Kellner HMKinetecs and metabolism of pyrazolones (propyphenazone, aminopyrine and dipyrone) . Br J Clin Pharmacol1980; 10: 299S-308S.
9.
Remmer H.Drug metabolism in the human liver measured with in vitro and in vivo methods . Arzneimittelforschung1976; 26: 1262-1263.
10.
Ortweiler W. et al. Die Elimination von Coffein and Metamizol zur in-vivo-Charakterisierung Cytochrom P-450-abhängiger Biotransformationsreaktionen beim alten Menschen. Pharmazie1985; 40: 787-790.
11.
Simon HU et al. Die Bestimmung der Coffein- und Metamizolelimination bei Männern and Frauen ohne sowie unter hormonalen Kontrazeptiva als in-vivo-Methode zur Charakterisierung verschiedener Cytochrom P-450 Subspezies. Pharmazie1985; 40: 50-52.
12.
Weiss R. et al. Vergleichende Untersuchungen zur Frage der Absorption and Metabolisierung des Pyrazolonderivates Metamizol nach oraler und intramuskulärer Gabe beim Menschen. Arzneimittelforschung1974; 24: 345-348.
13.
Imaoka S., Inoue K., Funae Y.Aminopyrine metabolism by multiple forms of cytochrome P-450 from rat liver microsomes: simultaneous quantitation of four aminopyrine metabolites by high-performance liquid chromatography. Arch Biochem Biophys1988; 265: 159-170.
14.
Van der Graaff M. et al. Correlation between the metabolism of hexobarbital and aminopyrine in vivo in rats. Xenobiotica1986; 16: 1091-1096.
15.
Matsuyama K. et al. Influence of phenobarbital and 3-methylcholanthrene on the metabolism of aminopyrine in isolated hepatocyte system. J Pharmacobio-Dynam1983; 6: 821-828.
16.
Gramatzki S.der 14C-Monomethylaminoantipyrin-Atemtest als in vivo-Parameter zur Charakterisierung der Induktion des arzneimittelabbauenden Enzymsystems beim Meerschweinchen. Inaugural-Dissertation, Freie Universität Berlin, 1981.
17.
Balogh A., Bode A., Hoffmann K.Disposition of dipyrone and its metabolites in man: influence of phenobarbital treatment and effects of cigarette smoking. Naunyn-Schmiedeberg's Arch Pharmacol1991; 343 (Suppl.): R122.
18.
Heinemeyer G. et al. Kinetics of hexobarbital and dipyrone in critical care patients receiving high-dose pentobarbital. Eur J Clin Pharmacol1987; 32: 273-277.
19.
Yanev S., Grahovska T., Stoytchev T.Analgineffects on liver drug metabolism. Symposium Drug Metabolizing Enzyme Systems, Sofia, May 20 - 22, 1986.
20.
Hoshi K. et al. Effect of repeated administration of monomethyl-aminoantipyrine on the activities of gamma-glutamyltranspeptidase and microsomal drug metabolizing enzymes in rat liver. Res Commun Chem Pathol Pharmacol1985; 48: 431-443.
21.
Hoshi K. et al. Enhancement of monomethylaminoantipyrine-induced increase of hepatic gamma-glutamyltranspeptidase activity by cobaltous chloride in rats . Res Commun Chem Pathol Pharmacol1986; 51: 81-88.
22.
Kraul H., Pasanen M., Pelkonen O.The effect of monoclonal antibodies on dipyrone-induced rat liver cytochrome P450. Arch Toxicol1991; 14 (Suppl): 194-198.
23.
Park SS et al. Monoclonal antibodies that inhibit enzyme activity of 3-methylcholanthrene-induced cytochrome P-450. Cancer Res1982; 42: 1798-1808.
24.
Park SS et al. Monoclonal antibodies to phenobarbital-induced rat liver cytochrome P-450. Biochem Pharmacol1984; 33: 2071- 2081.
25.
Bradford MMA rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem1976; 72: 248 - 254.
26.
Burke MD, Prough RA, Mayer RT Characteristics of a microsomal cytochrome P-448-mediated reaction ethoxyresorufin O-deethylation. Drug Metab Disposit1978; 5: 1-8.
27.
Pelkonen O. et al. The effect of cigarette smoking on 7-ethoxyresorufin O-deethylase and other monooxygenase activities in human liver: analyses with monoclonal antibodies. Br J Clin Pharmacol1986; 22: 125-134.
28.
Nebert DW, Gelboin HVSubstrate inducible microsomal aryl hydrocarbon hydroxylase in mammalian cell culture. I. Assay and properties of the induced enzyme. J Biol Chem1968; 243: 6242-6249.
29.
Aitio A.A simple and sensitive assay of 7-ethoxycoumarin deethylation. Anal Biochem1978; 85: 488-491.
30.
Omura T., Sato R.The carbon monoxide-binding pigment of liver microsomes. I. Evidence for its hemoprotein nature. J Biol Chem1964; 239: 2370-2378.
31.
Raunio H. et al. Mouse hepatic cytochrome P-450 isozyme induction by 1,4-bis(2-(3,5-dichloropyridyloxy))benzene, pyrazole, and phenobarbital. Biochem Pharmacol1988; 37: 4141-4147.
32.
Pasanen M. et al. Immunohistochemical detection of human placental cytochrome P-450-associated mono-oxygenase system inducible by maternal cigarette smoking . Placenta1988; 9: 267-275.
33.
Lubet RA et al. Dealkylation of pentoxyresorufin: A rapid and sensitive assay for measuring induction of cytochrome(s) P-450 by phenobarbital and other xenobiotics in the rat. Arch Biochem Biophy1985; 238: 43-48.
34.
Burke MD et al. Ethoxy-, pentoxy- and benzyloxyphenoxazones and homologues: A series of substrates to distinguish between different induced cytochromes P-450. Biochem Pharmacol1985; 34: 3337-3345.
35.
Prough RA, Burke MD, Mayer RTDirect fluorometric methods for measuring mixed-function oxidase activity . Methods in Enzymol1978; 52C: 376-377.
36.
Åström A., DePierre JWRat-liver microsomal cytochrome P-450: Purification, characterization, multiplicity and induction. Biochim Biophys Acta1986; 853: 1-27.
37.
Phillipson CE et al. Determination of cytochrome P-448 activity in biological tissues. Biochem J1984; 218: 81-88.
38.
Greenlee WF , Poland A.An improved assay of 7-ethoxycoumarin O-deethylase activity: induction of hepatic enzyme activity in C57BL/6J and DBA/2J mice by phenobarbital, 3-methylcholanthrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin . J Pharmacol Exp Therapeut1978; 205: 596-605.
39.
Raunio H. et al. Immunochemical and catalytical studies on hepatic coumarin 7-hydroxylase in man, rat, and mouse. Biochem Pharmacol1988; 37: 3889-3895.
40.
Slusher LB et al. Studies on the metabolism of aminopyrine, antipyrine and theophylline using monoclonal antibodies to cytochrome P-450 isozymes purified from rat liver. Biochem Pharmacol1987; 36: 2359-2367.
41.
Baron J., Redick JA, Guengerich FPAn immunohistochemical study on the localizations and distributions of phenobarbital- and 3-methylcholanthrene-inducible cytochromes P-450 within the livers of untreated rats. J Biol Chem1981; 256: 5931-5937.
42.
Bengtsson G. et al. Effect of phenobarbital on the distribution of drug metabolizing enzymes between periportal and perivenous rat hepatocytes prepared by digitonin-collagenase liver perfusion. J Pharmacol Exp Therapeut1987; 240: 663-667.
43.
Wolf CR et al. Characterization, localization and regulation of a novel phenobarbital-inducible form _ of cytochrome P450. compared with three further P450-isoenzymes, NADPH P450-reductase, glutathione transferases and microsomal epoxide hydrolase . Carcinogenesis1984; 5: 993-1001.
44.
Roots I., Ley B., Hildebrandt AGIn vivo parameters of drug metabolism - differences in specificity towards inducing agents. In: Microsomes and Drug Oxidations . Ullrich V et al. (eds). Pergamon Press , 1977.
45.
Park SS et al. Preparation and characterization of monoclonal antibodies to pregnenolone 16-α-carbonitrile inducible rat liver cytochrome P-450. Biochem Pharmacol1986; 35: 2859-2867.
