scholarly journals A comparison of the inhibitory effects of roxatidine acetate hydrochloride and cimetidine on cytochrome P-450-mediated drug-metabolism in mouse hepatic microsomes and in man in vivo.

1987 ◽  
Vol 10 (7) ◽  
pp. 287-295 ◽  
Author(s):  
KUNIHIKO MORITA ◽  
HIROKI KONISHI ◽  
TAKESHI ONO ◽  
HARUMI SHIMAKAWA
Keyword(s):  
Drug Metabolism ◽  
Inhibitory Effects ◽  
Roxatidine Acetate ◽  
Hepatic Microsomes ◽  
Cytochrome P 450 ◽  
Acetate Hydrochloride

scholarly journals Visualizing Drug Efficacy In Vivo

2005 ◽  
Vol 4 (2) ◽  
pp. 153535002005051 ◽  
Author(s):  
Weisheng Zhang ◽  
Min Chen ◽  
David B. West ◽  
Anthony F. Purchio
Keyword(s):  
Enzyme Activity ◽  
Drug Metabolism ◽  
Drug Effects ◽  
Study Drug ◽  
Drug Efficacy ◽  
Biochemical Assays ◽  
Metabolism Enzymes ◽  
First Time ◽  
Cytochrome P 450

Many enzymes are therapeutic targets for drug discovery, whereas other enzymes are important for understanding drug metabolism and pharmacokinetics during compound testing in animals. Testing of drug efficacy and metabolism in an animal model requires the measurement of disease endpoints as well as assays of enzyme activity in specific tissues at selected time points during treatment. This requires the removal of tissue and biochemical assays. Techniques to noninvasively assess drug effects on enzyme activity using imaging technology would facilitate understanding of drug efficacy, pharmacokinetics, and drug metabolism. Using a commercially available cytochrome P−450 3A substrate whose oxidized product is a luciferase substrate, we show for the first time that cytochrome P−450 enzyme activity can be measured in vivo in real time by bioluminescent imaging. This imaging approach could be applicable to study drug effects on therapeutic target enzymes, as well as drug metabolism enzymes.

Nonadditive effects of combined in vivo hepatic microsomal enzyme inducers in the Wistar rat

1983 ◽  
Vol 61 (9) ◽  
pp. 983-988 ◽  
Author(s):  
Larry S. Gontovnick ◽  
Geoffrey Sunahara ◽  
Gail D. Bellward
Keyword(s):  
Adult Female ◽  
Wistar Rat ◽  
Female Rats ◽  
Male Rats ◽  
Hepatic Microsomes ◽  
Trans Stilbene ◽  
Microsomal Enzyme Inducers ◽  
Nonadditive Effects ◽  
Cytochrome P 450

Compounds that are known to increase the hepatic microsomal cytochrome P-450 dependent monooxygenases were adminstered to adult female rats, alone or in combination, to determine whether their effects on certain substrate oxidations were additive. 3-Methyleholanthrene (3-MC) and pregnenolone-16α-carbonitrile (PCN), known to induce different forms of cytochrome P-450, when administered together increased benzo[a]pyrene oxidation to the same level as observed following 3-MC treatment alone. Phenobarbital (Pb) and PCN when administered concomitantly increased benzo[a]pyrene, aminopyrine, and ethylmorphine metabolism to the same extent as seen following PCN administration alone. Both compounds are known to induce different forms of cytochrome P-450. Nonadditive effects were also observed with Pb and spironolactone, as well as with Pb and trans-stilbene oxide. Treatment of adult male rats with either PCN or 3-MC resulted in significantly smaller increases in benzo[a]pyrene oxidation than observed in adult female rats. These results suggest that oxidative metabolism in hepatic microsomes is not the sum of activities of a number of cytochrome P-450s, but may represent the activity of a single predominant hemeprotein. In addition, it appears that the oxidation of substrate by a particular cytochrome P-450, in intact microsomes, is greatly influenced by the presence of another form.

scholarly journals Mechanistic studies of the inhibition of hepatic uroporphyrinogen decarboxylase in C57BL/10 mice by iron-hexachlorobenzene synergism

1986 ◽  
Vol 238 (3) ◽  
pp. 871-878 ◽  
Author(s):  
A G Smith ◽  
J E Francis ◽  
S J E Kay ◽  
J B Greig ◽  
F P Stewart
Keyword(s):  
Additional Treatment ◽  
Mechanistic Studies ◽  
Iron Species ◽  
Uroporphyrinogen Decarboxylase ◽  
Microsomal Cytochrome ◽  
Hepatic Microsomes ◽  
Iron Treatment ◽  
Maximum Inhibition ◽  
Cytochrome P 450

Porphyria was induced in C57BL/10 mice with iron overload by a single oral dose (100 mg/kg) of hexachlorobenzene (HCB). Within 2 weeks hepatic uroporphyrinogen decarboxylase (EC 4.1.1.37) was inhibited, reaching a maximum (greater than 95%) at 6-8 weeks. There was no recovery by 14 weeks, despite a fall in liver HCB concentrations to only 6% of the day-3 value. The major rise in hepatic porphyrin levels occurred after 4 weeks and secondary inhibition of uroporphyrinogen synthase (EC 4.2.1.75) was inferred from the progressively greater proportion of uroporphyrin I present relative to the III isomer. Plasma alanine aminotransferase (EC 2.6.1.2) activity was also elevated. Although, in further studies, total microsomal cytochrome P-450 content and ethoxyphenoxazone de-ethylase activity reached a peak a few days after dosing and had declined significantly at the time of maximum inhibition of the decarboxylase, additional treatment of HCB-dosed mice with a cytochrome P1-450 inducer, beta-naphthoflavone, enhanced the inhibition, whereas piperonyl butoxide, an inhibitor of cytochrome P-450, partially protected. Uroporphyrinogen decarboxylase was not radiolabelled in vivo by [14C]HCB. There was no major difference in the ability to hydroxylate HCB between hepatic microsomes from induced C57BL/10 mice and those from the insensitive DBA/2 strain. By contrast, lipid peroxidation, in the presence of NADPH, was 8-fold greater in control C57BL/10 microsomes than in DBA/2 microsomes and was stimulated by iron treatment (although not by HCB). The results suggest that the inhibition of hepatic uroporphyrinogen decarboxylase is unlikely to be due to a direct effect of a metabolite of HCB but to another process requiring a specific cytochrome P-450 isoenzyme and an unknown iron species.

scholarly journals Immunochemical detection of different isoenzymes of cytochrome P-450 induced in chick hepatocyte cultures

1989 ◽  
Vol 258 (1) ◽  
pp. 237-245 ◽  
Author(s):  
P Sinclair ◽  
J Frezza ◽  
J Sinclair ◽  
W Bement ◽  
S Haugen ◽  
...  
Keyword(s):  
Chick Embryo ◽  
Rabbit Antiserum ◽  
Enzyme Assays ◽  
Chick Embryos ◽  
Chemical Inducers ◽  
Hepatic Microsomes ◽  
Immunochemical Detection ◽  
Demethylase Activity ◽  
Cytochrome P 450

This study investigated whether the same cytochrome P-450 (P-450) isoenzymes were inducible in cultures of chick-embryo hepatocytes as in the liver of chicken embryos. We purified two isoenzymes of cytochrome P-450 from the livers of 17-day-old-chick embryos: one of molecular mass approx. 50 kDa induced in vivo by the phenobarbital-like inducer glutethimide, and the second of approx. 57 kDa induced by 3-methylcholanthrene. Rabbit antiserum against the 50 kDa protein inhibited benzphetamine demethylase activity in hepatic microsomes (microsomal fractions) from glutethimide-treated chick embryo. Antiserum to the 57 kDa protein inhibited ethoxyresorufin de-ethylase activity in hepatic microsomes from methylcholanthrene-treated chick embryo. Cultured chick hepatocytes were treated with chemicals known to induce isoenzymes of P-450 in rodent liver. The induced P-450s were quantified spectrophotometrically and characterized by immunoblotting and enzyme assays. From these studies, chemical inducers were classified into three groups: (i) chemicals that induced a P-450 isoenzyme of 50 kDa and increased benzphetamine demethylase activity: glutethimide, phenobarbital, metyrapone, mephenytoin, ethanol, isopentanol, isobutanol, lindane, lysodren; (ii) chemicals that induced a P-450 isoenzyme of 57 kDa and increased ethoxyresorufin de-ethylase activity: 3-methylcholanthrene and 3,3',4,4'-tetrachlorobiphenyl; and (iii) the mono-alpha-substituted 2,3',4,4',5-pentabromobiphenyl, which induced both proteins and both activities. The immunochemical data showed that chick-embryo hepatocytes in culture retain the inducibility of glutethimide- and methylcholanthrene-induced isoenzymes of P-450 that are inducible in the liver of the chicken embryo.

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