Induction of microsomal drug metabolizing enzymes by phenobarbitone in the rats exposed to increased environmental temperature.

Exposure of rats for 3 consecutive days (6 h a day) to 28 degrees C or 35 degrees C does not lead to changes in the induction of hepatic microsomal cytochrome P-450 associated monooxygenases by phenobarbitone as compared with control animals exposed to 21 degrees C. These results suggest that environmental temperature does not change the capacity of phenobarbitone to induce drug metabolizing enzymes in rat liver.

Effects of benzodiazepines on enzymes metabolizing drugs. IV. Effect of diazepam and oxazepam on hepatic microsomal drug metabolizing enzymes in rats exposed to high environmental temperature.

Administration of diazepam or oxazepam caused a different response of the rat hepatic microsomal cytochrome P-450 dependent monooxygenase system. Both drugs produced significant decrease in the activity of NADH: cytochrome c oxidoreductase in rats exposed to 21 degrees C, but not to 28 degrees C and 35 degrees C, and did not change the activity of aniline hydroxylase, aminopyrine N-demethylase and 4-nitroanisole O-demethylase and cytochrome b5 level at any tested temperatures. Oxazepam, but not diazepam, caused a decrease in cytochrome P-450 content in rats exposed to 21 degrees C only. The results indicate that the high ambient temperature modifies the effect of tested benzodiazepines on the activity of some microsomal enzymes.

[Benzodiazepines as cytochrome P-450 and cytochrome b5 inductors in rat liver microsomes]. / Benzodiazepiny jako induktory cytochromu P-450 i cytochromu b5 w mikrosomach watroby szczurów.

Among the benzodiazepines tested (diazepam, oxazepam, clonazepam, nitrazepam and chlordiazepoxide ) chlordiazepoxide is the most potent inducer of cytochrome P-450, diazepam is a poor inducer, whereas clonazepam and nitrazepam do not possess a capacity to induce of cytochrome P-450. On the other hand, microsomal cytochrome b5 is induced by diazepam only. The extent of induction of cytochrome P-450 and cytochrome b5 depends on the environmental temperature. Chlordiazepoxide is the most potent inducer of cytochrome P-450 in rats exposed to an ambient temperature of 28 degrees C, whereas diazepam have the highest induction ability in rats exposed to 35 degrees C. On the other hand, nitrazepam increased the content of cytochrome b5 in rats exposed to temperature of 35 degrees C only; diazepam was the most potent inducer of cytochrome b5 in rats exposed to temperature of 21 degrees C. These results indicate that high ambient temperature is a factor modifying the ability of benzodiazepines to induce of microsomal cytochrome P-450 and cytochrome b5.

[Structure and effects of benzodiazepines on hepatic microsomal monooxygenases in rats exposed to environmental temperature]. / Struktura benzodiazepin a ich dzialanie na mikrosomalne monooksygenazy watroby szczurów w podwyzszonej temperaturze otoczenia.

Five benzodiazepines (diazepam, oxazepam, clonazepam, nitrazepam and chlordiazepoxide) were compared with respect to their capacity to affect microsomal aniline hydroxylase, aminopyrine N-demethylase and 4-nitroanisole O-demethylase of rats exposed to the high ambient temperature of 28 degrees C or 35 degrees C. We have stated that the highest effect on the microsomal enzyme activities was observed after chlordiazepoxide, clonazepam or nitrazepam treatments. These results indicate that the presence of nitro group at position 7 or N-oxide at position 4 of benzodiazepine is important for the ability of benzodiazepines to affect the hepatic microsomal enzymes. High environmental temperature modifies the effect of benzodiazepines on tested microsomal enzymes.

[Effect of benzodiazepines on enzyme-metabolizing drugs. III. Activity of microsomal monooxygenases in the rat liver exposed to chlordiazepoxide and elevated environmental temperature]. / Dzialanie benzodiazepin na enzymy metabolizujace leki. III. Aktywnosc mikrosomalnych monooksygenaz watroby szczura w nastepstwie dzialania chlordiazepoksydu i podwyzszonej temperatury otoczenia.

It has been stated that elevation of environment temperature to 28 degrees C or 35 degrees C modifies effects of chlordiazepoxide on activities of rat liver microsomal enzymic systems involved in metabolism of xenobiotics: amidopyrine, aniline and 4-nitroanisole++.

Influence of increased environmental temperature on oxidation processes in rat liver mitochondria.

Exposure of rats to elevated temperature of 28 degrees C or 35 degrees C for 3 days six hours daily resulted in a decreased rate of oxidation with succinate or glutamate + malate as substrates, by the mitochondria of liver. The higher decrease was observed in environment temperature of 35 degrees C. There was no change in ADP/O ratio. The activities of NADH: cytochrome c reductase and cytochrome oxidase were stimulated but activities of succinate dehydrogenase and succinate cytochrome reductase were decreased.

Influence of repeated exposure to elevated environmental temperature on the activity of respiratory enzymes of rat liver mitochondria.

The paper presents studies of the activity of lipid-dependent enzymes of the respiratory chain of the liver of rats exposed to increased ambient temperature. The animals were heated in a chamber under controlled humidity (45-55% relative humidity), with forcer air flow and regulated temperature of 21 degrees +/- 1 degree C (control group) and 28 degrees +/- 1 degree C or 35 degrees +/- 1 degree C. They were affected by a relevant temperature for 7 or 14 consecutive days, 6 hrs daily. The enzymes activities were determined in a fraction of submitochondrial particles. The studies demonstrated that under the increased ambient temperature (7 X 6 hrs), the activity of the respiratory enzymes is changed. A statistically significant increase in the activity of NADH dehydrogenase, NADH cytochrome c reductase and cytochrome oxidase was found along with a decrease in the activity of succinate cytochrome c reductase and succinate dehydrogenase. On prolongation of thermal exposure (14 X 6 hrs) the activity of succinate dehydrogenase and succinate reductase: cytochrome c was further decreased. The activities of the other test enzymes did not exhibit any statistically significant differences as compared to controls. Kinetic tests of succinate dehydrogenase point to conformational changes of the enzyme when affected by an increased ambient temperature. This confirms the important role of this enzyme in the animals adaptation to thermally varying environmental conditions.

Liver and brain mitochondrial ATPase activities in rats exposed to high ambient temperature.

Liver and brain mitochondrial ATPase activities in rats exposed to high ambient temperature. Acta physiol. pol., 1985, 36 (3): 185-192. Rat liver and brain mitochondrial ATPase activities were investigated after a single exposure (6 h) of the animals to temperatures of 21 degrees, 28 degrees and 37 degrees C. An increase of ATPase activity stimulated by Ca++ ions was noted in the mitochondrial fractions of the liver at 28 degrees C and of the brain at 28 degrees and 37 degrees C. Only in liver mitochondria of rats exposed to 28 degrees C a depression of Mg++-ATPase activity was found.

Effects of phenobarbitone and short-term exposure to heat on microsomal cytochrome P-450 and associated monooxygenases in rat liver.

Short-term exposure of the control and phenobarbitone-treated rats to high ambient temperature caused a different response of the hepatic microsomal cytochrome P-450-dependent monooxygenase system participating in the oxidation of aniline, aminopyrine and p-nitroanisole. The highest differences of the enzyme activities were observed in rats exposed to 28 degrees C, as compared with animals exposed to 21 degrees C or 37 degrees C.

Activity of rat blood cholinesterases following exposure of the animals to increased environmental temperature.

The acetylcholinesterase activity of erythrocytes was investigated and compared with cholinesterase activity of the blood plasma in rats exposed to elevated temperature of the environment. The rats were kept in a thermic chamber with regulated temperature, forced air flow and controlled moisture of 55-19%. The applied temperatures were 21 degrees C (control) and 28 degrees C or 37 degrees C. The rats were exposed once for 3, 6, 12 or 24 hours and repeatedly for six successive days, for six hours each day. Experiments were also performed to find whether previous exposure of the rats to raised temperature "sensities" acetylcholinesterase to the action of typical cholinesterases inhibitor (DFP). Arrhenius plots were determined for erythrocyte acetylcholinesterase of rats subjected for 6 hours to raised temperature. It was found that the activities of both enzymes undergo only slight changes in dependence on the temperature applied and the time of exposure. More pronounced changes in this activity were observed when the rats were subjected to 37 degrees C. This may have been connected with disturbance of the lipoprotein structure and with an increase of osmotic fragility of the erythrocytes. It was also noted that earlier exposure of the animals to raised environmental temperature "sensitises" the acetylcholinesterase of the erythrocytes to the action of the organophosphorus inhibitor in vivo.

Respiratory activity and oxidative phosphorylation in mitochondria of the rat brain and liver under conditions of elevated temperature of the environment.

The rate of oxygen consumption by mitochondrial fractions of the brain and liver of rats under elevated ambient temperature was investigated. The animals were placed in a thermostatized chamber for 6 hours at 21 degrees, 28 degrees or 37 degrees C. During the experiment, relative humidity in the chamber was controlled. After exposure, the animals were decapitated, mitochondrial fractions isolated and oxygen consumption measured with the Clark electrode. Respiratory substrates of succinate and glutaminate with malate were used. The analysis of the obtained results was based on the t-Student test, assuming the values obtained for the animals staying at 21 degrees as the control values. It was found that the 6 hrs stay under the ambient hyperthermy conditions did not induce any disturbances in the respiratory processes and oxidative phosphorylation in rat's brain and liver mitochondria.

Hepatic microsomal mixed-function oxidases in rats exposed to high ambient temperature.

Exposure of rats for 3 h or 6h to 28 degrees C or 37 degrees C led to changes in mixed-function oxidases in liver microsomes as compared with 21 degrees C. The complex pattern of the behaviour of the activities of aniline hydroxylase, 4-nitroanisole-O-demethylase, aminopyrine N-demethylase and NADH: cytochrome c oxidoreductase was not related to the observed decrease of cytochrome P-450 and cytochrome b5 contents.

Modification of brain mitochondrial enzymes by the oxygen analogue of ronnel at various stages of development and aging.

This paper describes the effect of the organophosphorus compound, the oxygen analogue of ronnel (OAR), on the activity of some membrane-bound enzyme systems in the brain mitochondria of developing, young-adult, and old rats. Age-related changes were noted in the cholesterol-to-protein ratio, whereas the phospholipid content in mitochondria showed little change during development as well as aging. The results obtained suggest that development of brain succinate dehydrogenase may consist in a decrease of Km and increase of Vmax values. In aged rats an altered, perhaps inhibited form of the enzyme is produced. The oxygen analogue of ronnel caused a mixed-type inhibition of the succinate dehydrogenase derived from brains of 4-day-old, 16-day-old and 2-month-old animals. In the case of enzyme from the brain of 18-month-old rats, a typical competitive-type inhibition was observed. Mechanisms responsible for inhibition of the succinate: cytochrome c reductase from brains of developing animals are similar to those for succinate dehydrogenase. In aged rats (18 months old), however, a noncompetitive mechanism of inhibition of succinate: cytochrome c reductase was revealed. The experiments reported here provide evidence that lipid-soluble molecules of OAR may interact with membrane phospholipids and lead to modification of membrane architecture and also of enzyme kinetic behaviour. It may be also concluded, that the sensitivity of the enzyme systems studied to inhibition by OAR is an age-dependent phenomenon. Modification of membrane by development or aging alters the kinetics as well as the sensitivity of enzymes to inhibitors.