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Biomedical subjects

K J Netter

Publications and source records attributed to K J Netter.

At least 73 records · Page 4Linked to original sources
PubMed1979

Liver injury by the false morel poison gyromitrin.

After oral application of the mushroom poison gyromitrin a time and dose dependent decrease of cytochrome P-450 was found in rat liver microsomes. The maximal decrease to about 50-60% of the control (after 200 mg/kg, 80% of LD50) was observed 8-12h after application, a normalization after 48 h. The inhibition of cytochrome P-450 mediated metabolism of aminopyrine and p-nitroanisole corresponds to the decrease of cytochrome P-450. The specific activity of cytochrome P-450 remains unchanged while that of cytochrome P-448 is decreased as shown by means of the metabolism of ethoxycoumarin or ethoxyresorufin. Comparable results were obtained after application of N-methyl-N-formylhydrazine (MFH) which is formed from gyromitrin rapidly by hydrolysis. An attack on the endoplasmatic membrane with a stimulation of lipid peroxidation is discussed.

Acetaldehyde↗
PubMed1978

Significance of induction phenomena.

A number of foreign compounds induce the proliferation of the hepatic smooth endoplasmatic reticulum and thereby increase the activity of monooxygenases that metabolize drugs and other foreign compound. With reference to the safety of food additives some antioxidants have been examined by various authors for their inducing capacity, in doses well above those ingested with treated food and above the stipulated accepted daily intake (ADI). Thus feeding of rats with the very high dose of 500 mg/kg body weight of butylated hydroxtoluene (BHT) resulted in an increase in its own oxidative metabolism. Also in monkeys BHT produces an inductive increase of microsomal enzyme activity, cytochrome p 450, and a proliferation of smooth endoplasmatic reticulum. The closely related antioxidant butylated hydroxyanisole (BHA) leads to similar effects in mice. Recent studies with ethoxyquin (EQ) have shown that this antioxidant stimulates the formation of a form of cytochrome P 450 which resembles the phenobarbital-inducible type. EQ itself is also an inhibitor of mixed function monooxygenase. The naturally occuring flavouring agents safrole and isosafrole in high doses also induce hepatic monooxygenations. Spectroscopic examination has revealed, however, that another type of cytochrome with characteristic binding of a suspected safrole metabolite is produced. This complex shows absorption maxima at 427 and 455 nm and can be dissociated by adding a number of different lipophilic agents, including safrole itself. In a time dependent displacement reaction the characteristic spectrum decreases and is replaced by a classical binding spectrum of the displacer itself. By these examples it can be shown that food additives exert a number of effects on hepatic drug inactivating systems. However, no risk of hepatic changes can be seen from the small amounts of antioxidants ingested in balanced human nutrition.

Animals↗
PubMed1978

Differential inhibition of biphenyl hydroxylation in perfused rat liver.

A differential inhibition of biphenyl hydroxylation by alpha-naphthoflavone and metyrapone was observed in isolated perfused rat liver. alpha-Naphthoflavone inhibited 2- and 4-hydroxylation in livers from beta-naphthoflavone-pretreated animals but had no effect on both reactions in livers from phenobarbital-pretreated animals. Metyrapone inhibited 2- and 4-hydroxylation in phenobarbital-stimulated livers, but only insignificant inhibition of 2-hydroxylation and a slight enhancement of 4-hydroxylation by metyrapone was observed in beta-naphthoflavone-stimulated livers. Conjugation of 2-hydroxybiphenyl and 4-hydroxybiphenyl by isolated perfused livers was also studied. 4-Hydroxybiphenyl preferentially formed sulphates in livers from untreated animals but after induction glucuronidation was as effective as sulphation or even exceeded sulphation. Only glucuronic acid conjugates of 2-hydroxybiphenyl were detected.

Animals↗
PubMed1978

Reductive drug metabolism in isolated perfused rat liver under restricted oxygen supply.

1. Hepatic azo and nitro reductase activities were studied in the perfused rat liver under normal and restricted oxygen supply. 2. Formation of sulphanilamide or p-aminobenzoic acid from neoprontosil or p-nitrobenzoic acid under aerobic conditions of liver perfusion was negligible, even at a reduced oxygen saturation of a pO2 of 300 mm Hg in the haemoglobinfree perfusion system. At a pO2 of 200 mm Hg reductase activities were almost maximal. 3. Conjugation of sulphanilamide (0-08 mM) was similar under aerobic and anaerobic conditions. Hepatic elimination of p-aminobenzoic acid (0-08 mM) showed an oxygen-dependent increase for 15 min after addition of substrate. 4. p-Nitroanisole demethylation was inhibited 80% under hypoxic perfusion at 200 mm Hg pO2 and was completely inhibited after gassing with anoxic mixtures. 5. Restitution of aerobic conditions after 30 min anaerobic perfusion restored hepatic respiration, lactate pyruvate ratio, and pH value to levels found under aerobic conditions, but bile flow remained 50% reduced.

Animals↗
PubMed1978

Effect of nitrite on microsomal cytochrome P-450.

1. Addition of nitrite to anaerobic rat liver microsomes leads to the appearance of a difference spectrum similar to the spectrum of the ferrous cytochrome P-450-NO complex. A Soret band is found at 444 nm in phenobarbital-stimulated microsomes but at 442 nm in 3-methylcholanthrene-stimulated microsomes. An alpha-band is located at 583 nm in both types of microsome. 2. The initial nitrite-induced difference spectrum is converted into a spectrum lacking a Soret band but with a prominent absorbance minimum at 417 nm. This is more rapid in microsomes from phenobarbital-treated animals where it is completed in 8 min than in microsomes from 3-methylcholanthrene-treated animals. A similar spectrum can be obtained by addition of nitrite to urea-treated microsomes in which cytochrome P-450 has been converted to cytochrome P-420. 3. Azo cleavage of neoprontosil in anaerobic microsomes is markedly inhibited by 1 mM nitrite. In contrast, oxidative drug metabolism is affected only by very high nitrite concentrations around 100 mM. It is concluded that in anaerobic microsomes, NO formed from nitrite complexes with ferrous cytochrome P-450 and thereby inhibits reductive drug metabolism.

Animals↗
PubMed1978

Comparative bioavailability: influence of various diets on the bioavailability of indomethacin.

After oral application of 100 mg indomethacin to eight healthy male volunteers, the concentrations in plasma and their time course were determined when the drug was given to fasting individuals or after a high-protein, a high-lipid or a high-carbohydrate meal. The study was designed as a fourfold-crossover experiement with intermissions of at least one week between applications. Indomethacin in plasma was determined by fluorimetry after a double extraction procedure. Indomethacin plasma concentrations and the truncated areas under the curves (AUC) were evaluated. Administration to fasting subjects provides higher plasma levels and a smaller tmax value than after either one of the three diets. Also the absorption rate was higher in fasting individuals. However, the absorbed amount of indomethacin after 24 hr was practically equal in all four groups. Attempts to distinguish between the effects of the various diets revealed significant differences in the time period necessary to reach the peak values. After high-protein and high-lipid diets they were reached in the 90 min sample while after high-carbohydrate 120 min were required. These values are significantly different from fasting controls (45 min) and from each other. There is no great influence of food on the other aspect of bioavailability, amount of unchanged drug reaching the systemic circulation.

Adult↗
PubMed1977

Simultaneous determination of 4-nitroanisole, 4-nitrophenol, and 4-nitrocatechol by phase-sensitive ac polarography.

Phase-sensitive ac polarography was applied to the simultaneous quantitative determination of 4-nitroanisole, 4-nitrophenol, and 4-nitrocatechol in alkaline solutions. Certain experimental precautions are necessary to determine each compound in the presence of the other two. Thus, 4-nitrocatechol is determined indirectly by forming a yellow ratio chelate with cupric ions, wheras 4-nitroansole is determined directly by the reduction waves of the nitro group. For the determination of 4-nitrophenol, the interferency by the simultaneously present 4-nitrocatechol must be eliminated by masking it by the addition of magnesium ions. The method described permits a qualitative and quantitative analysis of all three compounds in one solution since linear calibration curves are obtained.

Anisoles↗
PubMed1977

Stimulation of hepatic microsomal metabolism in mice by a mixture of polybrominated biphenyls.

The pattern of stimulation of hepatic microsomal mixed function oxidases has been studied in female NMRI mice following a single ip injection of 150 mg/kg polybrominated biphenyls (PBBs) and compared to the patterns produced by phenobarbital (PB), 3 X 100 mg/kg; 3-methylcholanthrene (MC), 3 X 20 mg/kg; and these two agents administered together at these doses. Cytochrome P450, ethylmorphine N-demethylase, and epoxide hydratase reached maximums of 200, 200, and 350% of control values, respectively, at 48 hr after treatment with PBBs. Ethoxycoumarin O-deethylase and arylhydrocarbon hydroxylase were maximally increased to 400 and 180% of control values, respectively, 96 hr after PBBs. The reduced cytochrome P450 ethylisocyanide difference spectra and the inhibition of ethoxycoumarin O-deethylase and arylhydrocarbon hydroxylase activity by metyrapone and alpha-naphthoflavone indicated that the characteristics of the cytochrome P450 and the cytochrome P450-dependent enzymes changed with time after administration of PBBs. These results indicate that the enzyme-stimulating properties of PBBs alter, changing from PB-like to MC-like, with time after administration. These findings provide an explanation for the effects of PBBs on the toxicity of bromobenzene, indicating that PBBs represent a new and previously unrecognized calss of toxicity-modifying agents sharing properties of both PB and MC.

Animals↗
PubMed1977

Application of A. C.-polarography in a study of p-nitroanisole metabolism and its kinetic properties.

Phase sensitive alternating current polarography was introduced for the simultaneous determination of p-nitroanisole and its metabolites p-nitrophenol and p-nitrocatechol in kinetic studies with rat liver microsomes. The substrate p-nitroanisole disappears rather rapidly while p-nitrophenol is formed. First traces of a second oxidation product, p-nitrocatechol, can be detected only after a few minutes after the initiation of the reaction. This suggest that O-demethylation of p-nitroanisole is the primary reaction which is followed by aromatic ortho hydroxylation of p-nitrophenol. After incubation times longer than 15 minutes, appreciable amounts of p-nitrocatechol are found which shows optical absorption characteristics similar to those of p-nitrophenol (absorption maximum at 440 nm). It is concluded from these kinetic experiments that optical determination of the primary metabolite during the initial reaction phase constitutes a reliable measure of microsomal O-demethylation activity. Phenobarbital induction differentially increases O-demethylation and ring-ortho-hydroxylation activities. From this and respective inhibition studies it is concluded that possibly multiple forms of cytochrome P-450 are involved in the metabolism of either p-nitroanisole or p-nitrophenol.

Animals↗
PubMed1976

Errors in oxygen tension measurements caused by halothane.

Halothane, independent of oxygen tension, increased the signal of the gold/silver-silver chloride microelectrode. The output of microelectrodes at different oxygen tensions in the presence of increasing amounts of halothane has been measured. Halothane causes an increase in the electrode signal which is proportional to its concentration. This effect results from the polarographic reduction of halothane. It is concluded that the gold/silver-silver chloride microelectrode cannot be used to measure oxygen tension during halothane anaesthesia.

Anesthesia↗
PubMed1976

Effects of chronic administration of polybrominated biphenyls on parameters associated with hepatic drug metabolism.

Parameters relating to hepatic microsomal drug metabolism were measured in vitro following 2 weeks exposure of rats to polybrominated biphenyls (PBB) as a dietary supplement at 4.69, 18.75, 75 and 300 ppm. The mixture of PBB was a potent inducer of hepatic microsomal drug metabolism. The pattern of induction seen after PBB exposure was compared with that produced by phenobarbital and 3-methyl-cholanthrene and the pattern of induction observed shared similarities with both of these agents.

Animals↗
PubMed1975

The effects of sulphydryl reagents on the binding and mixed function oxidation of hexobarbital in rat hepatic microsomes.

1. The effects of the sulphydryl reagents p-chloromercuribenzoate, N-ethylmaleimide and iodoacetamide on the binding spectrum, oxygen consumption and formation of a suspected substrate-cytochrome P-450-oxygen complex for hexobarbital in rat liver microsomes were investigated. 2. The oxygen consumption caused by hexobarbital oxidation was inhibited non-competitively by all three agents, with 50% inhibition at 4 times 10(-5) M for p-chloromercuribenzoate, 3-7 times 10(-4) M for N-ethylmaleimide and 1-9 times 10(-3) M for iodoacetamide. Cysteamine protected and at least partially reversed this inhibition. 3. p-chloromercuribenzoate inhibited the formation of the cytochrome P-450-substrate-oxygen complex, while N-ethylmaleimide and iodoacetamide also inhibited the formation of this complex but to a lesser extent. The p-chloromercuribenzoate inhibition was protected against and reversed by cysteamine. 4. p-Chloromercuribenzoate and N-ethylmaleimide caused a 50% reduction in the magnitude of the hexobarbital-induced binding spectrum, and this was paralleled by the conversion of cytochrome P-450 to cytochrome P-420. Cysteamine protected against this effect but could not reverse it. Iodoacetamide had no effect on the binding spectrum of hexobarbital and failed to convert cytochrome P-450 to cytochrome P-420. 5. Points of attack within the reaction sequence of drug oxidation are tentatively ascribed to the sulphydryl reagents used in this study.

Animals↗