Search PubMed⌕ Search

Biomedical subjects

D V Parke

Publications and source records attributed to D V Parke.

At least 217 records · Page 12Linked to original sources
PubMed1975

Mechanism of induction of hepatic microsomal drug metabolizing enzymes by a series of barbiturates.

The inducing effect of certain barbiturates (secobarbitone, thiopentone, pentobarbitone, allobarbitone, phenobarbitone and barbitone) on the levels of the hepatic microsomal drug-metabolizing enzymes has been studied in the rat both in vivo and in vitro. The extent of induction was related to the plasma half-lives of the barbiturates; compounds with low rates of metabolism and long half-lives were the most potent inducing agents. The latter (phenobarbitone, pentobarbitone and allobarbitone) were shown by spectral technique to interact with cytochrome P-450 suggesting that their mechanism of enzyme induction was 'substrate induction' in type. Barbiturates containing an allyl group (secobarbitone and allobarbitone) had a weaker inducing effect than expected, possibly due to their destruction of cytochrome P-450. Despite its short plasma half-life of 0-5 h thiopentone was a relatively potent inducer probably due to its metabolism to pentobarbitone, which has a much longer plasma half-life (1-3 h). Barbitone is an effective inducer of the drug-metabolizing enzymes, yet does not interact spectrally with cytochrome P-450; this is in accord with the observations that although there are increases in NADPH-cytochrome c reductase and cytochrome b5, following administration of barbitone there is no increase in cytochrome P-450. Barbiturate pretreatment does not affect the activities of glucose-6-phosphatase, glucose-6-phosphate dehydrogenase or 6-phosphogluconate dehydrogenase.

Animals↗
PubMed1975

Effect of protein/energy nutrition on rat plasma corticosteroids and liver microsomal hydroxylase activity.

Three groups of 24-day-old male Wistar rats were fed (a) a control diet containing 210 g/kg protein ad libitum (control) (b) a low protein diet consisting of the stock diet diluted with starch to contain 70 g/kg protein ad libitum (protein deficient) or (c) an amount of stock diet containing the same amount of protein as eaten by (b) but without starch (energy deficient). The low protein diet did not affect the ability of the animals to metabolize biphenyl and excrete it as 4-hydroxybiphenyl, or reduce the total activity of 4-hydroxylase per liver, whereas this was reduced by restricted amounts of the high protein diet. The low protein diet resulted in raised levels of corticosteroids in the plasma. It is concluded that the raised specific activity, and unchanged total amount of biphenyl 4-hydroxylase per liver of the low protein animals is an adaptation to the diet mediated by corticosteroids as exogenous corticosteroids were also found to increase the activity of this enzyme in normal animals.

11-Hydroxycorticosteroids↗
PubMed1975

Effect of dietary substitution of sucrose and its constituent monosaccharides on the activity of aromatic hydroxylase and the level of cytochrome P-450 in hepatic microsomes of growing rats.

The effect of dietary substitution of starch by sucrose, glucose, fructose or an equimolar mixture of glucose and fructose on the activity of biphenyl hydroxylase and the level of the major terminal mixed function oxygenase, cytochrome P-450, has been studied in hepatic microsomal preparations from growing rats. The substitution of sucrose for starch depressed the contration and total activity per liver of biphenyl 4-hydroxylase and the concentration, but not the total amount, of cytochrome P-450 in weanling rats. The absolute amount of these enzymes in whole liver was not, however, similarly depressed by the constituents of sucrose, namely glucose and fructose, either when given alone or in equimolar mixture. All these sugars, however, depressed the total activity of biphenyl 2-hydroxylase. The activity of biphenyl 4-hydroxylase in the liver of weanling rats, but not of adults, was reduced when the level of sucrose in the diet was reduced from 60 to 10%.

Animals↗
PubMed1975

The effects of the non-ionic detergent Tween 80 on hepatic microsomal hydroxylation.

1. Effects of the non-ionic detergent Tween 80 on hamster liver microsomal components and on various reactions, including biphenyl hydroxylation, have been studied. Tween 80 competitively inhibited both 2- and 4-hydroxylation of biphenyl, with Ki values of 4-9 and 4-1 mM. The apparent kinetic constants corrected for the inhibitory effect of 2-9 mM Tween 80 (the concn. routinely used) were for 2-hydroxylation: Km = 0-47 mM, Vmax = 2-2 nmol/min/mg; and for 4-hydroxylation: Km = 0-14 mM, Vmax = 3-5 nmol/min/mg. 2. The type I spectrally apparent interaction of biphenyl with liver microsomes (Ks = 0-23 mM; deltaEmax = 8-2 E/2 mg protein) was also competitively inhibited by Tween 80 (Ki = 1-1 mM), itself an apparently type I substrate. 3. Tween 80 (9-5 mM) activated aniline 4-hydroxylation. The type II spectrally obvious interaction between aniline and microsomes was not affected by Tween 80. 4. Tween 80 and biphenyl together enhanced NADPH-cytochrome c reduction whereas Tween 80 and aniline together had no effect. Tween 80 did not affect the stability of cytochrome P-450 in microsomal suspensions over a 5 min period. 5. Results are discussed in terms of differences between biphenyl 2- and 4-hydroxylation systems, between type I and II substrate-enzyme complexes, and in terms of the relevance of spectral interactions to aryl hydroxylations.

Aniline Compounds↗
PubMed1975

Enhancement of hepatic microsomal drug metabolism in vitro following ethanol administration.

1. Administration of ethanol intraperitoneally at low dosages (10-25 mg/kg) to rats stimulates hepatic microsomal mixed-function oxidase activity in vitro. 2. Pretreatment with ethanol administered orally has no effect on in vivo drug metabolism as measured by pentobarbitone plasma half-life and has no effect on the excretion of ascorbic acid. Ethanol administration does not enhance its own binding to cytochrome P-450. 3. These observations suggest that the administration of ethanol, at moderate dosage, does not give rise to induction of hepatic cytochrome P-450. 4. Unwashed hepatic microsomes are contaminated with alcohol dehydrogenase, but pretreatment with ethanol does not increase microsomal generation of NADH. 5. Pretreatment with ethanol has no stimulatory effect on NADH-NADP+ transhydrogenation. 6. The stimulation of hepatic drug metabolism in vitro following administration of ethanol is not due to increased cytochrome P-450 nor to increased NADPH, per se, but appears to result from an increase in the activity of NADPH-cytochrome c reductase.

Animals↗