ABSTRACT
The ability of feprazone to induce the hepatic microsomal mixed-function oxidases was investigated in the rat, with emphasis being placed on the nature of the cytochrome P-450 family induced. Treatment with feprazone enhanced the p-hydroxylation of aniline and the dealkylations of benzphetamine and pentoxyresorufin but had no effect on the O-deethylation of ethoxyresorufin. The same treatment had no major effect on total cytochrome P-450 levels but increased the spectral interaction of metyrapone with reduced cytochrome P-450. Immunoblots employing monospecific polyclonal antibodies revealed that feprazone induces the apoprotein levels of the P450 II B, but not of the P450 I, family. It is concluded that feprazone is an inducer of the rat hepatic mixed-function oxidase system showing selectivity toward the P450 II B family.
Subject(s)
Cytochrome P-450 Enzyme System/biosynthesis , Feprazone/pharmacology , Phenylbutazone/analogs & derivatives , Animals , Antibodies , Body Weight/drug effects , Computer Simulation , Cytosol/enzymology , Enzyme Induction , Glutathione Transferase/metabolism , Immunoblotting , Liver/anatomy & histology , Liver/enzymology , Liver/ultrastructure , Male , Mixed Function Oxygenases/biosynthesis , Molecular Structure , NADP/metabolism , Organ Size/drug effects , Rats , Rats, Inbred StrainsABSTRACT
The ability of cimetidine to induce the hepatic microsomal mixed-function oxidases was investigated in rats treated orally with the drug at 3 dose levels: 10, 100 and 500 mg/kg. At the highest dose only, cimetidine stimulated the dealkylations of ethoxyresorufin, ethoxycoumarin and pentoxyresorufin but inhibited that of erythromycin and had no effect on the demethylation of dimethylnitrosamine. At the highest dose cimetidine had a small effect on the activation of Glu-P-1 to mutagens in the Ames test but induced proteins recognised in Western blots by antibodies to P450 I A1 and P450 II B1. It is concluded that cimetidine is a weak selective inducer of cytochrome P-450 forms, but at therapeutic doses its inductive effect is most unlikely to be of any clinical or toxicological consequence.
Subject(s)
Cimetidine/pharmacology , Microsomes, Liver/drug effects , Mixed Function Oxygenases/biosynthesis , Animals , Biotransformation , Cytochrome P-450 Enzyme System/biosynthesis , Dealkylation , Dose-Response Relationship, Drug , Enzyme Induction/drug effects , Imidazoles/metabolism , Male , Microsomes, Liver/enzymology , Mutagenicity Tests , Rats , Rats, Inbred StrainsABSTRACT
1. The effects of some possible inhibitors of ectonucleotidases on the breakdown of extracellular ATP by strips of guinea-pig urinary bladder were investigated. 2. Suramin and ethacrynic acid (10 mM) both inhibited ATP breakdown significantly, and difluorodinitrobenzene (10 mM) inhibited it slightly whereas N-ethylmaleimide, adenosine 5'-(gamma-thiotriphosphate) (ATP-gamma-S) and reactive blue-2 (10 mM) were without effect. 3. The inhibitory effects of suramin on ATP breakdown were non-competitive. 4. Ethacrynic acid (1 mM) irreversibly inhibited contractions of the guinea-pig bladder induced by ATP, substance P, histamine, non-adrenergic, non-cholinergic nerve stimulation or KCl, whereas suramin (100 microM) had no inhibitory effect. 5. The results suggest that suramin might provide a starting point for the design of selective inhibitors of ectonucleotidases.
