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K J Netter

Publications and source records attributed to K J Netter.

At least 55 records · Page 3Linked to original sources
PubMed1987

Mechanisms of monooxygenase induction and inhibition.

The mechanisms of monooxygenase induction and inhibition have been discussed from the standpoint of historic development, from the current concepts about the molecular mechanism of enzyme induction, and from the various possibilities by which inhibitors can interact with the complex cytochrome P-450 monooxygenase system. In detail the main features and phenomena of induction and of the induced new enzyme protein are briefly described, whereby general principles are emphasized. The current knowledge on the mechanism of induction is exemplified by a description of the inducing action of TCDD on mouse hepatoma cells. A special example of increase in the molecular activity towards 7-ethoxycoumarin-0-deethylation is given by the action of sulmazole on mouse liver cytochrome P-450. It possesses properties similar to that of cobaltous chloride in that it decreases the amount of cytochrome P-450 in the microsomal protein but at the same time increases the molecular activity to about a four-fold level. The mechanisms of inhibition of the microsomal monooxygenase are explained in general terms by outlining the various modes of inhibitory action that lead to a decrease in enzyme activity.

Enzyme Induction↗
PubMed1985

Induction of liver cytochrome P-450 in mice by warfarin. Comparison of warfarin-, phenobarbitone-, and cobalt-induced hepatic microsomal protein patterns by PAGE after partial purification on octyl-sepharose CL-4B.

A rapid method is presented to separate mouse liver cytochrome P-450 from other components of the microsomal monooxygenase system and to increase specific activity by hydrophobic interaction chromatography on Octyl-Sepharose CL-4B by a factor of between 3.8 and 5.3. In addition it is shown that varieties of cytochrome P-450 can be separated from each other by Octyl-Sepharose CL-4B. After oral applications of 120 mg/kg warfarin once daily for three days SDS-PAGE analysis of the partially purified cytochrome P-450 fraction revealed a protein pattern in the 50 Kd region that is practically indistinguishable from that after conventional phenobarbitone pretreatment. On the other hand, cobalt pretreatment results in a different pattern that is distinguished from that of normals as well as from that of phenobarbitone- and warfarin-pretreated mice. From these results in conjunction with the previous finding of increased drug metabolic activity after warfarin pretreatment it is concluded that warfarin elicits phenobarbitone-like induction of the hepatic monooxygenases in mice.

Animals↗
PubMed1984

Inhibition of the uptake of nucleosides in cultured Harding-Passey melanoma cells by diflubenzuron.

Diflubenzuron (DFB) significantly inhibited the uptake of uridine, adenosine, and cytidine but not thymidine, in cultured Harding-Passey melanoma cells. Inhibition of nucleoside uptake was rapid (i.e., less than or equal to 5 min) and could not be reversed by washing. These results suggest that DFB may affect membrane properties and - as shown by in vivo tests - growth of melanoma cells.

Animals↗
PubMed1984

Effects of vanadate on intracellular reduction equivalents in mouse liver and the fate of vanadium in plasma, erythrocytes and liver.

Intraperitoneal injection of 180 mumol sodium vanadate/kg body wt in mice inhibits the in vivo metabolism of drugs by the hepatic monooxygenase, as measured by exhalation of 14CO2 after treatment with appropriately labeled [14C]methacetin. Determinations of hepatic GSH, NADPH and NADH after vanadate injection show an initial and transient decrease of GSH (10 min, 20%), followed by a transient decrease of NADPH (30 min, 23%), followed by a decrease of NADH (40 min, 23% and 60 min, 26%). Rat liver organ spectrophotometry in the dual-wavelength mode shows an immediate response of the NAD(P)H level, which decreases transiently after addition of vanadate. Furthermore, EPR and AAS measurements indicate that vanadium occurs in the plasma in the oxidation states +IV and +V, whereas in intracellular compartments in liver and erythrocytes vanadium exists practically only in the +IV form (vanadyl). The duration of the inhibition for about 2 h coincides well with the transient concentration of vanadate in plasma, which decreases more rapidly than vanadyl. Maximal drug inhibition is associated with the phase of rapid formation of vanadyl in the liver. The experiments are in accordance with the hypothesis that vanadate inhibits the cytochrome P-450 dependent oxidative drug metabolism by diversion of reducing equivalents away from cytochrome P-450. Further evidence for such a hypothesis is provided by in vitro experiments in microsomes. Vanadate causes a dose dependent decrease of ethoxyresorufin deethylation which is reversible by the addition of NADPH.

Acetamides↗
PubMed1983

Vanadium inhibits oxidative drug demethylation in vivo in mice.

Sodium vanadate inhibits the oxidative demethylation of substrates of the cytochrome P-450-dependent monooxygenase system in vivo in mice. [14C]Methacetin and 7-[methoxy-14C] coumarin were used as substrates, and the exhaled 14CO2 was monitored using the technique of the breath test. The inhibition is of short duration and begins to subside after about 10 min. The inhibition is dose-dependent; half-maximal effect is achieved at a dose of approximately 60 mumol/kg. The inhibition pattern is identical for both substrates, although 62% of the label of [14C] methacetin and only 10% of 7-[methoxy-14C] coumarin are enhaled within 1 h. Pretreatment with ascorbic acid (50 mg/kg p.o.) drastically diminishes the observed inhibitory effect of vanadate. Similarly, application of an equimolar dose of vanadyl sulphate produces a comparatively weak retardation of 14CO2 exhalation. The effect of vanadate is thought to occur by its competition for electrons normally transferred to cytochrome P-450.

Acetamides↗
PubMed1982

Does cobalt pretreatment of mice induce a phenobarbitone-type cytochrome P-450?

1. Pretreatment of male C57BL/6JHan mice with 40 mg/kg cobaltous chloride for two days, or three days pretreatment with 80 mg/kg phenobarbitone led to an increase of biphenyl-4-hydroxylation of similar magnitude. 2-Hydroxylation remains unaffected in both cases. 2. The time course shows an equivalent decrease in 2- and 4-hydroxylation for 6 h, when microsomal Co concn, reaches its maximum. Thereafter 4-hydroxylation increases to reach the enhanced values. 3. Kinetic analysis of biphenyl 2- and 4-hydroxylation reveals distinct differences. The apparent Km for 4-hydroxylation decreases in Co-pretreated mice but remains constant in phenobarbitone-pretreated animals. Also, the ratio of 4- to 2-hydroxylation in microsomes from phenobarbitone-treated animals remains unchanged for substrate concn. of 10(-5) to 2 X 10(-3) m, but for Co-pretreatment this ratio increases markedly from 2 to 5, with increasing substrate concn. 4. Increasing concn. of the competitive inhibitor, metyrapone, reveal a greater susceptibility of microsomal cytochrome P-450 from Co-treated mice than normal or phenobarbitone-induced animals. In contrast, deprivation of reducing equivalents in vitro in the presence of metyrapone shows similarities between microsomes from cobalt- and phenobarbitone-pretreated mice.

Animals↗
PubMed1982

[Influence of the mushroom poison gyromitrin on the lipids of rat liver (author's transl)].

Gyromitrin, the main poison of the false morel Gyromitra esculenta, causes enlargement of the liver in rats. The content of triglycerides and total cholesterol were increased in the liver homogenate and microsomal fraction but not in the mitochondrial fraction. On the other hand the content of phospholipids was found to be decreased. The enhanced incorporation of [14c]-acetate into the lipids of rat livers after gyromitrin indicates an increased rate of lipids synthesis. The diminution of the phospholipids is caused mainly by a loss of phosphatidyl ethanolamine (PE) although after a short pulse with [14C]-ethanolamine the specific radioactivity of the isolated phosphatidyl ethanolamine corresponded to that of the controls. Since the content of phosphatidylcholine (PC) remained unchanged, the PC/PE-ratio was shifted from 2.3 to 4.5. These effects were reversible within 48 h. Inhibition of the synthesis of highly unsaturated fatty acids by the microsomal monoxygenase system is discussed as the primary reason for the above observations this inhibition possibly being due to active metabolites of gyromitrin which destroy the monoxygenases.

Acetaldehyde↗
PubMed1981

The toxicology of 1-acetyl-2-methyl-2-formyl hydrazine (Ac-MFH).

The hepatotoxic and cancerogenic N-methyl-N-formyl hydrazine (MFH), which is formed from the mushroom poison, gyromitrin, by hydrolytic cleavage in vivo and in vitro during food processing, loses its hepatotoxicity and its influence on the renal function of rats after acetylation at the free NH2-moiety. The importance of MFH-acetylation with regard to an inhibition of microsomal conversion of MFH into a toxic nitrosamide is considered. The known genetically determined heterogeneity of the acetylation rate for hydrazine derivates in man may explain the observed differences in sensitivity towards the mushroom toxins.

Animals↗
PubMed1980

Characteristics of coumarin metabolism by liver microsomes from cobalt-pretreated mice.

1. Cobalt pretreatment of male mice leads to increased liver microsomal mixed-function oxidation of various coumarin derivatives; 7-ethoxycoumarin, 7-hydroxycoumarin and coumarin are metabolized three to four times more rapidly than in control microsomes. 2. In Arrhenius plots of 7-ethoxycoumarin de-ethylation, the temperature at which phase transition occurs is not changed by cobalt pretreatment. However, at high temperature, above the transition point, the slope indicates that cobalt lowers the apparent activation energy of the reaction to 65% of control value. 3. Metabolism of 7-hydroxycoumarin by hepatic microsomes from cobalt-treated mice gave 3,7- , 6,7- and 7,8-dihydroxycoumarin, identified by g.l.c. and mass spectrometry.

Animals↗