The effect in vivo and in vitro of allylisopropylacetamide on the content of hepatic microsomal cytochrome P-450 2 of phenobarbital treated rabbits

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.

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Metabolic activation of acetylenic substituents to derivatives in the rat causing the loss of hepatic cytochrome P-450 and haem

Biochemical Journal ◽

10.1042/bj1740853 ◽

1978 ◽

Vol 174 (3) ◽

pp. 853-861 ◽

Cited By ~ 51

Author(s):

Ian N. H. White

Keyword(s):

Covalent Binding ◽

Metabolic Activation ◽

Microsomal Protein ◽

Significant Loss ◽

Microsomal Cytochrome ◽

Rf Values ◽

Green Pigments ◽

Cytochrome P 450

1. A number of acetylenic-substituted steroidal and non-steroidal compounds, including 2,2-dipropargylacetamide, pregna-2,4-dien-20-yno[2,3-d]isoxazol-17-ol (Danazol) and acetylene gas, when administered to rats in vivo brought about a decrease in the concentrations of hepatic microsomal cytochrome P-450 and haem. Abnormal haem-breakdown products, ‘green pigments’, and porphyrins accumulated in the livers of these animals. 2. For loss of microsomal cytochrome P-450 to occur in vitro, metabolic activation of the acetylenic substituent was necessary. The enzyme system responsible required NADPH and air, and was induced by pretreatment of rats with phenobarbitone; these are characteristics typical of the microsomal mixed-function oxidases. 3. When rats were dosed with 17α-ethynyl-17β-hydroxyandrost-4-en-3-one (ethynyltestosterone, 1mmol/kg) the pattern of green pigments extracted from the liver 4h after dosing and separated by t.l.c. was quite different from that in rats given 17β-hydroxy-17α-vinylandrost-4-en-3-one (vinyltestosterone), suggesting that reduction of the unsaturated triple bond to a double bond is not normally part of the metabolic activation pathway of the acetylenic substituent. 4. The green pigments extracted from the livers of rats 4h after the administration of the acetylenic-substituted compounds (1mmol/kg) when separated by silica-gel t.l.c. had variable RF values. The number and distribution of green pigments was characteristic for each compound examined. There was little correlation between the total loss of hepatic microsomal haem and the apparent intensity of the green pigments seen on the thin-layer chromatograms. 5. After incubation of [14C]acetylene in vitro with microsomal preparations from phenobarbitone-pretreated rats and a NADPH-generating system, no significant covalent binding to microsomal protein was detected over a 30min incubation period, although under similar conditions there was a significant loss of cytochrome P-450.

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Interaction of monocrotophos and its novel thion analogues with microsomal cytochrome P-450: in vivo and in vitro studies in rat

Toxicology ◽

10.1016/0300-483x(92)90160-g ◽

1992 ◽

Vol 76 (2) ◽

pp. 133-139 ◽

Cited By ~ 5

Author(s):

M.K.J. Siddiqui ◽

M. Mahboob ◽

M. Mustafa

Keyword(s):

In Vitro Studies ◽

Microsomal Cytochrome ◽

Cytochrome P 450

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The protective properties of synthetic porphyrin tin complexes in toxic hyperbilirubinemia

Journal of Porphyrins and Phthalocyanines ◽

10.1002/(sici)1099-1409(200004/05)4:3<243::aid-jpp201>3.0.co;2-d ◽

2000 ◽

Vol 04 (03) ◽

pp. 243-247 ◽

Cited By ~ 9

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.

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

Zeitschrift für Naturforschung C ◽

10.1515/znc-1991-9-1031 ◽

1991 ◽

Vol 46 (9-10) ◽

pp. 906-914 ◽

Cited By ~ 12

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.

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