scholarly journals N-alkylation of the haem moiety of cytochrome P-450 caused by substituted dihydropyridines. Preferential attack of different pyrrole nitrogen atoms after induction of various cytochrome P-450 isoenzymes

1983 ◽  
Vol 211 (2) ◽  
pp. 455-461 ◽  
Author(s):  
F De Matteis ◽  
A H Gibbs ◽  
C Hollands
Keyword(s):  
Isomeric Composition ◽  
Structural Isomers ◽  
Ethyl Group ◽  
Cytochrome P 450 ◽  
Pyrrole Nitrogen

1. 3,5-Diethoxycarbonyl-4-ethyl-1,4-dihydro-2,6-dimethylpyridine (4-ethyl-DDC) gives rise to N-ethylprotoporphyrin in the liver of rats by donating its 4-ethyl group to one of the pyrrole nitrogen atoms of haem. Four structural isomers are obtained, depending on which pyrrole nitrogen is alkylated. 2. When rats are pretreated with an inducer of cytochrome P-450, the production of N-ethylprotoporphyrin caused by 4-ethyl-DDC is greater, both in the whole animal and in hepatocytes incubated with the drug in vitro. 3. Pre-incubation of hepatocytes with 2-allyl-2-isopropylacetamide decreases the yield of N-ethylprotoporphyrin due to 4-ethyl-DDC, an effect largely reversed by adding exogenous haem. 4. The isomeric composition of N-ethylprotoporphyrin produced in vivo and in vitro depends on the cytochrome P-450 isoenzyme that predominates at the time of treatment, suggesting a role for the apo-cytochrome in directing alkylation on to one of the pyrrole nitrogens.

The protective properties of synthetic porphyrin tin complexes in toxic hyperbilirubinemia

2000 ◽  
Vol 04 (03) ◽  
pp. 243-247 ◽  
Author(s):  
T. O. PHILIPPOVA ◽  
B. N. GALKIN ◽  
N. YA. GOLOVENKO ◽  
Z. I. ZHILINA ◽  
S. V. VODZINSKII
Keyword(s):  
Heme Oxygenase ◽  
Serum Bilirubin ◽  
Protoporphyrin Ix ◽  
Serum Bilirubin Level ◽  
Oxygenase Activity ◽  
Tetraphenyl Porphyrin ◽  
Tin Complexes ◽  
Cytochrome P 450

Tin complexes of meso-substituted synthetic porphyrins, namely Sn 4+-meso-tetraphenyl- porphyrin ( Sn - TPP ) and Sn 4+-meso-tetrakis(N-methyl-3-pyridyl)porphyrin tetratosylate ( Sn - TMe -3- PyP ), efficiently decrease the serum bilirubin level when injected subcutaneously at a dose of 100 μM kg−1 body weight into mice. These compounds are active during hyperbilirubinemia, induced by phenylhydrazine, hemin and tetrachloromethane, and also during autoimmune hemolytic anemia. In the latter case a decrease in serum bilirubin content was observed, as well as a decrease in the amount of blood reticulocytes which reflects a milder course of the disease. The Sn complexes under study induce, in vivo, cytochrome P-450, inhibit microsomal heme oxygenase and decrease the intensity of lipid peroxidation. At the same time, in vitro the hepatic and splenic heme oxygenase activity is blocked only when a 0.1 μM concentration of Sn - TMe -3- PyP or Sn -protoporphyrin IX is added to the incubation mixture. Sn - TPP does not affect the activity of this enzyme in vitro.

Influence of Safeners on the in vivo and in vitro Metabolism of Bentazon and Metolachlor by Grain Sorghum Shoots: a Preliminary Report

1991 ◽  
Vol 46 (9-10) ◽  
pp. 906-914 ◽  
Author(s):  
Donald E. Moreland ◽  
Frederick T. Corbin
Keyword(s):  
Grain Sorghum ◽  
In Vitro Studies ◽  
Naphthalic Anhydride ◽  
Surface Sterilization ◽  
Polar Components ◽  
In Vitro Shoots ◽  
Treated Seed ◽  
Cytochrome P 450

Abstract Metabolism of bentazon and metolachlor by excised shoots and a microsomal fraction iso­lated from the shoots, of 3-day-old, dark-grown, grain sorghum (Sorghum bicolor cv. Funk G 522 DR) seedlings was studied. The effects of seed treatments, on the subsequent metabo­lism of the herbicides, with the safeners naphthalic anhydride, oxabetrinil, and CGA 133205 were compared against surface-sterilization and Captan-treatments. Bentazon was aryl hydroxylated in both in vivo and in vitro studies with the hydroxylated derivative undergoing glycosylation only under in vivo conditions. Both shoots and microsomes isolated from shoots of safener-treated seed showed enhanced metabolism of bentazon relative to the controls. In­ hibition by tetcyclacis, a potent inhibitor of plant cytochrome P-450 monooxygenases, in both the in vivo and in vitro studies, and a requirement for NADPH in the in vitro studies suggested that the formation of hydroxybentazon was mediated by a cytochrome P-450 monooxygenase. Metolachlor was metabolized to polar material and O-desmethylmetolachlor under in vivo conditions. Only the demethylated product was formed in vitro. Shoots isolated from safener-treated seed showed enhanced formation of polar com pounds which were assumed to have arisen from conjugation with glutathione. Tetcyclacis did not affect the formation of the polar components. However, the formation of O-desmethylmetolachlor was depressed in the shoots excised from safener-treated seed under both in vivo and in vitro conditions. Tetcyclacis completely prevented formation of the demethylated metabolite. Hence, formation of this meta­bolite is considered to be P-450 mediated. The differential response obtained with the safeners, i.e., stimulation of aryl hydroxylation of bentazon and depression of metolachlor demethylation, suggests that the reactions are probably catalyzed by different cytochrome P-450 mono­oxygenases.

Identification of human cytochrome P 450 s that metabolise anti-parasitic drugs and predictions of in vivo drug hepatic clearance from in vitro data

2003 ◽  
Vol 59 (5-6) ◽  
pp. 429-442 ◽  
Author(s):  
Xue-Qing Li ◽  
Anders Bj�rkman ◽  
Tommy B. Andersson ◽  
Lars L. Gustafsson ◽  
Collen M. Masimirembwa
Keyword(s):  
Hepatic Clearance ◽  
Human Cytochrome ◽  
Cytochrome P 450 ◽  
Vitro Data ◽  
In Vitro Data

Alterations of Hepatic Microsomal Drug Metabolism by Glucagon

1975 ◽  
Vol 53 (5) ◽  
pp. 873-879 ◽  
Author(s):  
Jacob V. Aranda ◽  
Kenneth W. Renton
Keyword(s):  
Substrate Oxidation ◽  
Type I ◽  
Nadph Cytochrome ◽  
Transport Chain ◽  
Hexobarbital Sleeping Time ◽  
Nadph Oxidation ◽  
In Vivo Effects ◽  
Cytochrome P 450

The effect of glucagon on the components of the hepatic microsomal electron transport chain (NADPH oxidase, NADPH cytochrome c reductase (EC 1.6.2.4), cytochrome P-450, and NADPH cytochrome P-450 reductase), and on two representative oxidative pathways (aminopyrine N-demethylation, a type I substrate oxidation; and aniline p-hydroxylation, a type II substrate oxidation) was determined. Microsomes from rats pretreated with glucagon (300 μg/kg per day for 3 days) showed a significant decrease in NADPH oxidation and in aminopyrine N-demethylation with a prolonged hexobarbital sleeping time, and a significant increase in aniline p-hydroxylation. Microsomes from rats pretreated with a lower dose of glucagon (30 μg/kg per day for 3 days) showed a significant decrease in the microsomal N-demethylation of aminopyrine. Glucagon had no effect when added in vitro to microsomes, suggesting that the in vivo effects of glucagon are mediated indirectly in the intact animal.

Effect of Chronically Administered Ketoconazole on the Elimination of Theophylline in Man

1987 ◽  
Vol 21 (6) ◽  
pp. 514-517 ◽  
Author(s):  
James J. Heusner ◽  
George E. Dukes ◽  
Douglas E. Rollins ◽  
Keith G. Tolman ◽  
Raymond E. Galinsky
Keyword(s):  
Multiple Dose ◽  
Statistical Difference ◽  
Dosage Adjustment ◽  
Serum Concentrations ◽  
Fluorescence Polarization Immunoassay ◽  
Metabolic Processes ◽  
Time Points ◽  
Cytochrome P 450

Ketoconazole, a nitrogen-substituted imidazole, has been shown to be a potent in vitro inhibitor of cytochrome P-450-mediated metabolic processes. Conflicting reports exist concerning the in vivo effect of ketoconazole on concomitantly administered drugs that require these metabolic processes for clearance. Therefore, the effect of multiple-dose ketoconazole on the elimination of theophylline, a drug metabolized by cytochrome P-450, in ten healthy, nonsmoking males (aged 18–40 years) was evaluated. Each subject received aminophylline 6 mg/kg iv before and at the end of seven days of ketoconazole 200 mg/d po. Theophylline serum concentrations were determined by fluorescence polarization immunoassay (TDx) at 12 time points over the 24-hour period following each infusion. No statistical difference (two-tailed t-test) in half-life (mean ± SD 7.8 ± 1.8 vs. 8.2 ± 1.9 h) or clearance (0.797 ± 0.201 vs. 0.722 ± 0.133 ml/min/kg) could be demonstrated for theophylline before or after ketoconazole administration. Theophylline dosage adjustment is probably not necessary for concomitant theophylline and ketoconazole drug therapy.

Cytochrome P-450 Inhibition Blocks Bone Resorption In Vitro and In Vivo

1999 ◽  
Vol 120 (1) ◽  
pp. 84-91 ◽  
Author(s):  
Moo-Jin Choo ◽  
Richard A. Chole
Keyword(s):  
Bone Resorption ◽  
Cytochrome P 450

Cytochrome P-450 and Peroxidase Oxidize Detoxication Products of Carcinogenic Aristolochic Acids (Aristolactams) to Reactive Metabolites Binding to DNA in vitro

1995 ◽  
Vol 60 (12) ◽  
pp. 2189-2199 ◽  
Author(s):  
Marie Stiborová ◽  
Eva Frei ◽  
Heinz H. Schmeiser ◽  
Manfred Wiessler
Keyword(s):  
Dna Adducts ◽  
Microsomal Cytochrome ◽  
Aristolochic Acids ◽  
Nuclease P1 ◽  
Order Of Magnitude ◽  
Prostaglandin H ◽  
Cytochrome P 450

We report the analysis of DNA adducts formed from aristolactams I and II, which are the final metabolites derived from carcinogenic aristolochic acids in vivo, after their oxidation by microsomal cytochrome P-450 and horseradish peroxidase in vitro. DNA adducts were detected and quantified using the nuclease P1-enhanced variation of the 32P-postlabeling assay. Quantitative analysis revelead that the extent of modification of DNA by aristolactams activated by peroxidase was more than one order of magnitude higher than for activation by microsomal cytochrome P-450. Peroxidase catalyzes the formation of active oxygen in the presence of NADH, H2O2 and aristolactams. Aristolactams are also oxidized by mammalian peroxidase prostaglandin H synthase. The possible role of aristolactams in carcinogenesis induced by aristolochic acid is discussed.

scholarly journals Decreased liver cytochrome P-450 in rats caused by norethindrone or ethynyloestradiol

1977 ◽  
Vol 166 (1) ◽  
pp. 57-64 ◽  
Author(s):  
I N H White ◽  
U Muller-Eberhard
Keyword(s):  
Marked Effect ◽  
Enzyme System ◽  
Time Dependent ◽  
Female Rats ◽  
Liver Cytochrome ◽  
Mixed Function Oxidases ◽  
Green Pigments ◽  
Cytochrome P 450

1. 19-Nor-17alpha-pregna-1,3,5(10)-trien-20-yne-3,17-diol (ethynyloestradiol) or 17beta-hydroxy-19-nor-17alpha-pregn-4-en-20-yn-3-one (norethindrone) but not 17alpha-ethyl-17beta-hydroxy-19-norandrost-4-en-3-one (norethandrolone) caused a time-dependent loss of cytochrome P-450 when incubated in vitro with rat liver microsomal fractions and NADPH-generating systems. 2. The enzyme system catalysing the norethindrone-mediated loss of cytochrome P-450 had many characteristics of the microsomal mixed-function oxidases. It required NADPH and air, and was inhibited by Co. However, it was unaffected by 1 mM-compound SKF 525A. 3. In microsomal fractions from phenobarbitone-pretreated rats the norethindrone-mediated loss of cytochrome P-450 was increased relative to controls. The norethindrone-mediated cytochrome P-450 loss was less pronounced when the animals were pretreated with 3beta-hydroxy-pregn-5-en-2-one 16alpha-carbonitrile (pregnenolone 16alpha-carbonitrile). Pretreatment with 3-methylcholanthrene rendered the animals resistant to the norethindrone effect. 4. Administration in vivo [100mg/kg, intraperitoneally] of norethindrone or ethinyl oestradiol also produced a time-dependent loss of liver cytochrome P-450. Norethandrolone had a similar, though much less-marked, effect. All three steroids lead to an induction of 5-aminolaevulinate synthase and an accumulation of porphyrins in the liver. 5. The loss of cytochrome P-450 and the accumulation of porphyrins in the liver 2 h after the administration of norethindrone to female rats was similar to that seen in males. 6. Rats pretreated with phenobarbitone and given norethindrone or ethynyloestradiol (100mg/kg, intraperitoneally) formed green pigments in their livers. These had characteristics similar to the green pigments produced in the livers of rats after the administration of 2-allyl-2-isopropylacetamide. No green pigments could be extracted from the livers of control rats or those given norethandrolone, oestradiol or progesterone.

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