Effect of typical inducers of microsomal drug-metabolizing enzymes on phospholipid metabolism in rat liver.
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Animals↗
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Effects of inhibitors of aldehyde metabolizing enzymes on putrescine metabolism in guinea pig liver homogenates [proceedings].
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Acetaldehyde↗
Plasma clearance of propranolol and sotalol and hepatic drug-metabolizing enzyme activity.
The role of hepatic drug-metabolizing enzyme activity for plasma propranolol and sotalol levels was investigated in 68 patients with hypertension or angina pectoris by comparing elimination rate with antipyrine kinetics and cytochrome P-450 content in the liver. All subjects were resistant to or had hepatotoxic reaction to previous treatment. Plasma antipyrine clearance and cytochrome P-450 content in biopsies were related to propranolol elimination from plasma, the best fit being obtained with the clearance values. Sotalol plasma clearance was not related to any indirect or direct reflector of the hepatic drug-metabolizing enzyme system. The results demonstrate that plasma clearance of the short-acting beta blocker, propranolol, depends on the activity of hepatic drug-metabolizing enzyme system and indicates a trial with a drug such as sotalol which is not dependent on liver metabolizing capacity.
Adult↗
Proliferation of smooth endoplasmic reticulum and induction of microsomal drug-metabolizing enzymes after ether or halothane.
Hepatic drug-metabolizing enzymes and hepatic ultrastructure were studied in rats after two hours of anesthesia with 1 MAC halothane or diethyl ether. Twelve hours after cessation of either anesthetic smooth endoplasmic reticulum was increased in centrilobular but not in periportal hepatocytes. This change persisted at 24- and 36-hour sampling times. Microsomal cytochrome P450 and cytochrome b5 decreased after halothane anesthesia (by 7 to 20 per cent of control). Diethyl ether caused increased cytochrome P450 and cytochrome b5 (27 and 18 per cent, respectively) at the 36-hour sampling time. NADPH cytochrome c reductase did not change significantly after either agent. The authors interpret these results to mean that both agents promote conversion of rough endoplasmic reticulum to smooth endoplasmic reticulum or, alternatively, that the anesthetics decrease degradation of smooth endoplasmic membranes. Since only ether caused an increase in the microsomal content of enzymes of the drug-metabolizing enzyme system, it is concluded that these two anesthetics act on hepatic cells by dissimilar mechanisms.
Animals↗
Amino acid metabolizing enzymes in rat submaxillary gland, normal or neoplastic, and in pancreas.
The activities of 12 enzymes, many related to ornithine metabolism, were measured in rat submaxillary gland, submaxillary gland tumors and pancreas. In submaxillary gland, the activities of arginase, ornithine aminotransferase, pyrroline-5-carboxylate reductase and glutamine synthetase were high, but no ornithine transcarbamylase or proline oxidase could be detected. In the fetal submaxillary gland, arginase was at almost adult levels while ornithine aminotransferase reached 50% of its adult value postnatally. Submaxillary tumors deviated from their cognate tissue by lower levels of amino acid metabolizing enzymes and by high concentrations of thymidine kinase. In pancreas, none of the pyrroline-5-carboxylate metabolizing enzymes were as high as in either liver or submaxillary gland. The outstanding activities were those of gamma-glutamyl transpeptidase and glutamate dehydrogenase. Although arginase activities in submaxillary gland and pancreas were quantitatively similar, they differed qualitatively: submaxillary gland contained the same variant as liver while the pancreatic isozymes resembled those of other nonhepatic tissues.
Amino Acids↗
Effects of insulin, tolbutamide, and glucagon on activities of jejunal carbohydrate-metabolizing enzymes in humans.
The activities of jejunal carbohydrate-metabolizing enzymes show adaptive drugs, and sex hormones. To learn whether insulin, tolbutamide, and glucagon had effects on these enzymes, we performed serial peroral jejunal biopsies in normal young men and in obese patients, before and after treatment with these agents. Jejunal mucosa was assayed for glycolytic enzyme activities, pyruvate kinase (PK), hexokinase (HK), and fructose-1,6-diphosphate aldolase (FDPA), and the nonglycolytic enzyme activity, fructose diphosphatase (FDPase). Insulin significantly increased the activity of jejunal PK (+48% change from control) and HK (+6%), decreased the activity of FDPase (-36%),and had no effect on FDPA. Glucagon had opposite effects; the activity of PK was decreased (-33%) and FDPase was increased (+50%). Tolbutamide significantly increased the activities of PK (+47%), HK (+14%), and FDPA (+7%), and decreased the activities of FDPase (-36%). The results of tolbutamide on glycolytic enzyme activities were independent of endogenous insulin. The data support the concept that jejunal carbohydrate-metabolizing enzymes in man respond to hormones and drugs similar to responses observed in rat liver. This is important because it now gives us a means of studying the actions of these hormones directly in human tissue.
Adolescent↗
Circadian variations in microsomal drug-metabolizing enzyme activities in rat and rabbit tissues.
1. The circadian variations in drug-metabolizing enzyme activities have been measured in microsomal fractions from the livers, lungs, and intestines of rabbits and in the livers and intestines of rats. 2. Circadian rhythms in enzyme activities in the rat intestine show 2 peaks in activity (around 0500 and 1900 h) with two intermediate troughs around 1200 and 2400 h. This twin-peaked (biphasic) profile contrasts with the single maximum and minimum in activity observed in rat liver. 3. Rabbit hepatic, pulmonary, and intestinal microsomal drug-metabolizing enzyme activities also show a biphasic profile during a 24 h period. This profile is less distinct in liver than in intestine, and less distinct in intestine than in lung. Consequently, rat and rabbit hepatic drug metabolizing enzyme activities show a considerable species difference with respect to their circadian profiles in activity.
Animals↗
Inducibility of mucosal drug-metabolizing enzymes of rats fed on a cholesterol-rich diet by polychlorinated biphenyl, 3-methylcholanthrene and phenobarbitone.
The results show that a cholesterol-rich diet changes the composition of mucosal membranes. A high cholesterol diet increases mucosal cholesterol and phospholipid contents. Cholesterol enhanced mucosal NADPH cytochrome c reductase and aryl hydrocarbon hydroxylase activities as well as mucosal UDP glucuronosyltransferase activity. When phenobarbitone or Clophen A 50 or 60 were administered intraperitoneally to cholesterol-fed rats, the hydroxylation and glucuronidation activities decreased to a lower level. 3-Methylcholanthrene was, however, able to maintain or increase mucosal hydroxylative enzymes and UDP glucuronosyltransferase. These results indicate that the drug-metabolizing enzymes of the intestinal mucosa behave very differently from those in the liver. Diet apparently has a regulatory effect on the induction of drug-metabolizing enzymes because only a very potent inducer, 3-methylcholanthrene, was able to maintain and even induce mucosal drug-metabolizing enzymes in rats fed on a high cholesterol diet, possibly through changes in the microenvironment of enzymes caused by cholesterol.
Animals↗
Role of neonatal androgen in the development of hepatic microsomal drug-metabolizing enzymes.
The development of several hepatic microsomal drug-metabolizing enzyme activities in rats was studied in relation to its androgen dependence during the neonatal period. Rats with their androgen deprived during the neonatal period (female rats and male rats castrated at birth) respond less to androgen treatment at adulthood for the metabolism of aminopyrine, ethylmorphine and hexobarbital as compared to rats exposed to neonatal androgen (male rats, male rats castrated at birth but neonatally treated with androgen and male rats castrated at the age of 20 days). This difference in the degree of hepatic responsiveness, however, varied with the substrates: ethylmorphine N-demethylase activity was affected the most whereas aminopyrine N-demethylase and hexobarbital oxidase activities were only marginally affected. Furthermore, these differences in responsiveness seem to be a delayed event, since hepatic aminopyrine N-demethylase activity in rats castrated at birth did respond to androgen stimulation during the prepubertal period and became insensitive to this same androgen stimulation at adulthood. The effect of neonatal androgen on the apparent Michaelis constant (Km) of ethylmorphine N-demethylase was also studied in the adult rat. Rats castrated at birth had a Km value (0.75 plus or minus 0.15 mM) similar to that of the females (0.95 plus or minus 0.13 mM). However, rats castrated at birth but neonatally treated with androgen and rats castrated at the age of 20 days exhibited Km values (0.29 plus or minus 0.06 and 0.25 plus or minus 0.06 mM, respectively) similar to that of the males (0.35 plus or minus 0.15 mM). The significance of neonatal androgen in the development of hepatic microsomal drug metabolizing enzyme system is discussed.
Aminopyrine N-Demethylase↗
Biochemical properties of some microsomal xenobiotic-metabolizing enzymes in rabbit small intestine.
Comparison of xenobiotic-metabolizing enzymes in rabbit small intestinal and hepatic microsomal fractions showed mainly quantitative differences; most of the activities were two to seven times higher in liver than in intestine. However, UDP-glucuronyltransferase activity was higher in intestine than in liver. The apparent absence of benzene hydroxylase in small intestine was the only qualitative difference noticed. Aniline hydroxylase, aminopyrine N-demethylase, and aryl hydrocarbon dydroxylase were characterized in intestinal microsomes and compared to those of liver. Distribution of these enzymes along the entire length of small intestine showed that maximum activities of the enzymes were present in the proximal 60 cm of the intestine. All the enzymes in both tissues required NADPH and O2 for maximum activity and were inhibited by cytochrome c, SKF 525-A, and CO. The in vitro addition of drug substrates to microsomal fractions of both tissues produced typical type I and type II binding spectra. Comparison of the relationships between activities and pH, duration of incubation, and substrate and protein concentration suggested that the rabbit intestinal and hepatic xenobiotic-metabolizing enzymes studied have similar characteristics.
Aminopyrine N-Demethylase↗
A comparative study of some more important experimental animal peroxide metabolism enzymes.
1. We have studied and compared the peroxide metabolism enzymes (SOD, P and C) of the main organs of fresh-water mollusc, chicken, mouse, guinea-pig, rabbit, cat and dog. 2. The liver exhibited the highest SOD activity. The enzymatic activities of the organ homogenates of the guinea-pig stand out in comparison with the values for the other homogenates examined. 3. The liver, kidney and total brain homogenates of the chicken and the vertebrates display no, or only a very low P activity. The highest P activities were measured in the haemolysates. 4. The C and SOD values exhibit a certain parallelism. 5. The peroxide metabolism enzyme activities calculated by utilizing the protein measurements permit the establishment of a more realistic enzymatic activity.
Animals↗
Effect of dietary lipid on drug-metabolizing enzymes.
Male rats fed diet containing 3% corn oil for 3 weeks metabolized hexobarbital, aniline and heptachlor significantly faster than those fed fat-free diet. Half-maximal changes in aniline hydroxylation occurred in rats fed corn oil at approximately 0.1% of calories, whereas half-maximal changes in hexobarbital oxidase and heptachlor epoxidase occurred in rats fed corn oil at 1 to 1.5% of calories. Kinetic measurements of the drug-metabolizing enzyme system in washed microsomes revealed that maximal rate of aniline and ethylmorphine metabolism in male rats occurred with 3% corn oil diet, whereas maximal rate for hexobarbital occurred with 10% corn oil diet. In female rats maximal aniline hydroxylation occurred in rats receiving 10% corn oil diet. No alterations in Km for these reactions were observed in male or female rats fed 3% corn oil but were increased in rats fed 10% corn oil for those substrates whose maximal rate of metabolism was also increased (i.e., hexobarbital in males and aniline in females). Thus qualitative changes in microsomal drug-metabolizing enzymes may occur in rats ingesting diets containing 10% corn oil. Associated with the increased drug metabolism in corn oil-fed rats were increases in concentration of cytochrome P-450 in male and female rats, decreased sleeping time in male rats, and decreased glucose 6-phosphate dehydrogenase activity of male and female rats. No change in NADPH cytochrome c reductase activity was observed. Spectral binding measurements revealed increases in substrate binding associated with increased metabolism, most of which could be ascribed to the increases in cytochrome P-450. The spectral dissociation constant for these interactions between drug and oxidized cytochrome P-450 was unaltered with the exception that it was decreased in female rats fed 10% corn oil diet. Evidence of qualitative changes in the enzymes of endoplasmic reticulum was limited to those associated with an altered fatty acid composition of phospholipid and changes in the ethylisocyanide difference spectrum of reduced microsomes.
Aniline Hydroxylase↗
Acrylamide gel electrophoretic studies of extracellular sucrose-metabolizing enzymes of Streptococcus mutans.
This study explored the use of acrylamide gel electrophoretic methods to determine the numbers and types of extracellular sucrose-metabolizing enzymes produced by particular strains of S mutans. Strains HS-6, SL-1, FA-1, and NCTC 10449 were cultured in a chemically defined medium and the extracellular proteins elaborated by the organisms were isolated and subjected to acrylamide gel electrophoresis. Patterns of protein components and sucrose-metabolizing enzymes were then delineated. Three types of sucrose-metabolizing enzymes were observed. One type was involved in the synthesis of polysaccharides that were insolubilized in the gels. Another type was involved in the synthesis of water-soluble polysaccharides. A third type was involved in the splitting of sucrose into reducing sugars without polysaccharide synthesis. Each pattern was distinctive with regard to the numbers, proportions, and types of enzyme components present and their migratory characteristics. From two to at least six components were observed amont the enzyme activity patterns per strain. Extracellular protein patterns showed from 12 to 20 components per strain. Comparative data on growth in the chemically defined medium and Todd-Hewitt broth were also presented. Better growth levels were obtained in all instances with the chemically defined medium over comparable periods of time.
Culture Media↗
Effect of "drugs for liver disease" on hepatotoxic action of carbon tetrachloride. II. Effect of protoporphyrin and phosphorylcholine on microsomal drug-metabolizing enzyme activities and the components in injuried liver.
The effect of "drugs for liver disease", protoporphyrin (PP) and phosphorylcholine (PC), on CCl4-induced liver injury was studied. Attention was given to the levels of microsomal drug-metabolizing enzyme and lipolytic enzyme activities and of some microsomal components such as phospholipid and peroxides. Administration of PP to CCl4-poisoned rats was found to increase the decreased microsomal drug-metabolizing enzyme activities, aminopyrine N-demethylase, aniline p-hydroxylase, cytochrome P-450 and b5 and lipolytic enzyme activity in CCl4-poisoned liver (12-20% increase as compared with those of the poisoned rats), and returned to control levels earlier than in CCl4-poisoned rats. Furthermore, administration of PP to CCl4-poisoned rats caused a decrease in the lipid peroxidation. A single dose of PP to normal rats was shown to increase these parameters, to a small extent. One of the mechanisms may be attributed to the fact that PP increases the biosynthesis of the hemoproteins by means of the incorporation of PP into the pigments and protects the membranes from lipid peroxides and the free radicals. On the other hand, administration of PC to the poisoned rats did not enhance the levels of the drug-metabolizing enzyme activities except for aminopyrine N-demethylase. Phospholipid phosphorous content, however, increased by 13-14% when PC was given. Thus, it is considered that PC may enhance the reconstitution of phospholipids in the injured membrane.
Aminopyrine N-Demethylase↗
Inhibition of hepatic drug-metabolizing enzymes by arachidonic acid.
1. The effects of arachidonic acid on hepatic drug-metabolizing enzymes was investigated in male ICR-Swiss mice. 2. A single administration of arachidonic acid, 100 mg/kg i.p., doubled the hexobarbital sleeping time. Arachidonic acid in vitro gave a type I binding spectrum with hepatic microsomes; it inhibited the metabolism of hexobarbital and of ethylmorphine, two type I binding drugs, but not that of aniline, a type II binding drug; the inhibition of hexobarbital metabolism by arachidonic acid was competitive. 3. Repeated administration of arachidonic acid up to a total dose of 1000 mg/kg i.p., either in the course of 5 hours, or in the course of 5 days, decreased microsomal cytochrome P-450 levels and NADPH-cytochrome c reductase activity. 4. It is concluded that the administration of arachidonic acid may impair drug metabolism in two ways, mainly, by competitively inhibiting the activity of drug-metabolizing enzymes, and secondarily, by decreasing the hepatic concentration of these enzymes.
Animals↗
Selective induction of liver drug-metabolizing enzymes in rats exposed to a 21 ATA He-O2 environment.
The effects of prolonged exposure to a hyperbaric environment (21 ATA He-O2, 200 +/- 300 mm Hg O2, 32.5 +/- 1 degrees C) were investigated on the activity of rat liver drug-metabolizing enzyme systems, as monitored by O-dealkylation and N-dealkylation reactions. Continuous exposure of different groups of rats to a hyperbaric environment for 8, 22, 39, 57, or 84 d significantly increased the in vitro activity of drug-metabolizing enzymes in liver preparations obtained from rats subjected to prolonged exposures. The increase in the in vitro O-dealkylation of p-nitroanisole was selective; and the percent increases were 27, 146, 58, 40, 49, and 44 in liver preparations obtained from rats exposed continuously for 8, 22, 39, 57, 72, or 84 d, respectively. On the other hand, no statistically significant increase was observed in the in vitro activity of rat liver drug-metabolizing enzyme preparations during N-dealkylation of morphine and cocaine.
Animals↗
Inhibition of hepatic drug-metabolizing enzymes by thiophaophate insecticides and its toxicological evaluation.
Thiophosphate insecticides, fenitrothion, diazinon and methylparathion, inhibit hepatic drug-metabolizing enzyme activity which was assayed using aminopyrine and aniline as substrates. About 50% inhibition was observed 4 hrs after the injection of fenitrothion into mice in a dose of 25 mg/kg. The addition in vitro of thiophosphates into a reaction mixture of drug metabolizing enzyme also produced an effective inhibition and IC50 was around 10(-5)M for fenitrothion. DDVP and oxygenated metabolite of fenitrothion did not show any inhibiting effect either in vitro or in vivo. The inhibition of thiophosphates in vitro was competitive while the kinetics of in vivo inhibition was shown as non-competitive. The drug metabolism in the rat liver preparation was also inhibited by thiophosphate in vitro, but in vivo treatment to male rats resulted in only slight inhibition. Female rats exhibited the similar response as mice. The administration of fenitrothion to mice prolonged the hexobarbital sleeping time and, consequently, suppressed the oxidative metabolism of parathion in liver preparation. These effects reveal that the biological half life of thiophosphate insecticides could be altered by the mode of administration or by co-existing thiophosphates.
Aminopyrine N-Demethylase↗
Endotoxic glycolipid as a potent depressor of the hepatic drug-metabolizing enzyme systems in mice.
Inhibitory effects of the endotoxic glycolipid from Salmonella minnesota R595 on hepatic drug-metabolizing enzyme activities in mice were investigated, and the depressor activity of the glycolipid in the enzyme systems was confirmed. Among degradation products of lipopolysaccharides tested, lipid A preparations derived from the mild acetic acid hydrolysates of lipopolysaccharides were the most active, but the lipid A fractions prepared from the hydrolysates with 1 N-HCl were almost inactive. A degraded polysaccharide fraction from E. coli lipopolysaccharide was inactive. The activities of the glycolipid and the lipid A preparation were markedly reduced by treatment with alkaline-hydroxylamine, mild alkali or hydrazine. The data showed that the lipid A moiety of the glycolipid may be responsible for the inhibitory activity on the hepatic drug-metabolizing enzyme systems.
Aminopyrine N-Demethylase↗