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Biomedical subjects

K W Renton

Publications and source records attributed to K W Renton.

At least 19 recordsLinked to original sources
PubMed1992

The suppression of hepatic cytochrome P4504A mRNA mediated by the interferon inducer polyinosinic acid.polycytidylic acid.

Interferon and interferon inducers are well known to depress the cytochrome P450-dependent hepatic mixed-function oxidase system and cause a decrease in the capacity of the liver to metabolize drugs and xenobiotics. In this study we have shown that the interferon-mediated changes in an induced form of hepatic cytochrome P450 (CYP4A) are mediated via a depression in the levels of mRNA as assessed by Northern blot and slot blot analyses using a 20-base synthetic oligodeoxyribonucleotide hybridization probe. Rats were pretreated with clofibrate to maximize CYP4A mRNA levels prior to the administration of polyinosinic acid.polycytidylic acid (poly IC), an alpha/beta interferon inducer. Hepatic CYP4A mRNA levels were decreased by 49 and 30% at 6 and 24 hr, respectively, following poly IC administration. In hepatic microsomes cytochrome P450 and functional CYP4A as measured by lauric acid hydroxylation, were not affected at 6 hr, but were depressed by 39 and 27%, respectively, 24 hr following poly IC administration. These results suggest that interferon depresses induced levels of hepatic drug metabolism by lowering the level of cytochrome P450 mRNAs and subsequent synthesis of cytochrome P450 apoproteins.

Animals↗
PubMed1991

Surfactant-potentiated increases in intracranial pressure in a mouse model of Reye's syndrome.

Severe encephalopathy, the usual cause of death in Reye's syndrome (RS), is characterized by cerebral edema with associated increases in intracranial pressure (ICP). In previous studies, we have shown that exposure of neonatal mice to nontoxic doses of an industrial surfactant and subsequent infection with mouse-adapted influenza B (Lee) virus result in a significant increase in mortality rate and that this is associated with several of the characteristic features of human RS. In the present study we have measured ICP in the young mice undergoing their version of the disease, and we now report that the animals treated with surfactant plus virus experience increases in intracranial pressure that are significantly in excess of those in any of the three control groups. These findings support our hypothesis that this and the other abnormal biochemical and morphological responses in RS are related in some manner to a chemically compromised host.

Animals↗
PubMed1991

The effect of IFN-alpha-Con1 on hepatic cytochrome P-450 and protein synthesis and degradation in hepatic microsomes.

Interferon and its inducers are well known to depress drug biotransformation in the liver by decreasing the levels of cytochrome P-450 in that organ. We now report that IFN-alpha-Con1, which was constructed from the most frequently observed amino acid sequences in human alpha-interferon subtypes, causes a loss in cytochrome P-450 which could be prevented by pretreating animals with either puromycin or actinomycin D. This suggests that the loss in drug biotransformation is mediated via the production of an intermediate protein. When the turnover of microsomal protein was examined this interferon appeared to depress the synthesis of proteins with molecular weights 46-60 kd and had little effect on the synthesis of other proteins. The in vitro translation of proteins of molecular weights 45-60 kd was also depressed in an in vitro translation system using mRNA isolated from the livers of interferon treated hamsters. Interferon had no effect on the degradation of microsomal proteins of all molecular weights. It is concluded that interferon probably depresses the levels of cytochrome P-450 in the liver by decreasing the synthesis of the apoprotein and that interferon has little effect on the degradation of the hemoprotein.

Animals↗
PubMed1991

Factors involved in the depression of hepatic mixed function oxidase during infections with Listeria monocytogenes.

A number of infections are capable of depressing the capacity of the liver to metabolize drugs. We have studied a number of factors which could be involved in the depression of cytochrome P-450 and related drug biotransformation enzymes during infections with Listeria monocytogenes. During the course of the infection, drug metabolism and heme content of hepatic microsomes were depressed but heme oxygenase was elevated. A free radical scavenger alpha-tocopherol did not prevent the loss and xanthine oxidase activities did not correlate with the time course of the loss. Infections in susceptible (balb/c) mice produced a larger loss in drug metabolism than in resistant (C57BL/6) mice, and an avirulent strain of the bacteria was without effect. A preparation of hemolysin isolated from Listeria monocytogenes produced a dose-dependent loss of cytochrome P-450 in isolated hepatocytes. These experiments indicate that the loss of drug metabolism during Listeria infections is most likely due to hemolysin released by the bacteria.

Animals↗
PubMed1991

A role for xanthine oxidase in the loss of cytochrome P-450 evoked by interferon.

It has been suggested that the loss of cytochrome P-450, which is mediated by interferon and its inducers, can result from the generation of free radical species by the enzyme xanthine oxidase. Cytochrome P-450, aminopyrine N-demethylase, and ethoxyresorufin deethylase were depressed by 35, 36, 38%, respectively, in the livers of hamsters 24 h following the administration of a synthetic interferon (IFN-alpha-Con1) which contains the most frequent amino acid sequences of the human subtypes. Interferon increased the activities of the D and O forms of xanthine oxidase by 65 and 74%, respectively, in the same animals. The induction of the D form of xanthine oxidase, which is the precursor of the O form, preceded the loss in cytochrome P-450. The protein synthesis inhibitor, actinomycin D, prevented the interferon-induced loss of drug biotransformation and the increase in xanthine oxidase. The free radical scavenger, alpha-tocopherol, and the xanthine oxidase inhibitor, allopurinol, also prevented the loss of cytochrome P-450 mediated by the interferon inducer poly rI.rC. In chickens in which xanthine oxidase cannot be formed, poly rI.rC had no effect on cytochrome P-450 levels. These results suggest that xanthine oxidase induction may play some role in the interferon-mediated loss of cytochrome P-450.

Allopurinol↗
PubMed1990

Distribution of delta-aminolevulinic acid synthetase and delta-aminolevulinic acid dehydratase in liver and kidney of rainbow trout (Salmo gairdnerii).

1. Activities of delta-aminolevulinic acid synthetase (ALA-S) and delta-aminolevulinic acid dehydratase (ALA-D) in trout liver and kidney were compared with those in the mouse. 2. ALA-S activity (per unit tissue fresh weight) exceeded ALA-D activity in trout liver and kidney. 3. In trout kidney, ALA-S activity slightly exceeded, and ALA-D activity far exceeded, their activities in trout liver. 4. In trout, heme synthesis differs from that in mammals in that appreciable synthesis occurs in the kidney, and in that ALA-S activity is not rate limiting.

5-Aminolevulinate Synthetase↗
PubMed1990

Regulation of hepatic cytochrome P-450 during infectious disease.

During episodes of infectious disease the mixed function oxidase system is depressed and the capacity of the liver to metabolize drugs can be compromised in both animals and humans. The depression that occurs during viral infections is mediated via the production of interferon. This action of interferon requires the synthesis of an intermediate protein(s) yet to be identified. Using an oligonucleotide probe for a unique sequence in cytochrome P-450LA omega we have now shown that the mRNA for this isozyme is depressed following the administration of interferon inducers. The magnitude in the loss of mRNA corresponds to the magnitude of the loss in the levels of this isozyme. This depression is observed within 6 h of interferon exposure. It is concluded that the decrease in drug metabolism during viral infections is caused by an interferon-mediated loss in mRNA and subsequent cytochrome P-450 synthesis in the liver.

Cytochrome P-450 Enzyme System↗
PubMed1988

High-dose caffeine and cardiac rate and rhythm in normal subjects.

In a previous 24-hour study of the electrophysiologic effects of moderate dose caffeine (1 mg/kg body weight/half-life), we found a significant (p less than 0.01) increase in ventricular ectopic beat (VEB) frequency among 18 patients with preexisting primary ventricular dysrhythm (mean 207 +/- 350 VEBs/hour, no caffeine, versus 307 +/- 414 VEBs/hour, caffeine). We also found a statistically insignificant (NS) increase in the incidence of infrequent VEBs in 18 normal control subjects (four of 18, no caffeine vs nine of 18 caffeine). Because of the high risk of beta-error among the previously-studied normal control subjects, we tested another group of 34 normal subjects, 15 males and 19 females with a mean age of 31 years (range 21 to 49 years), using a higher dose of caffeine. All subjects abstained from caffeine for 72 hours and had a control 24-hour Holter ECG recorded between hours 48 and 72. Caffeine half-life was calculated for each subject and caffeine was then ingested at 1 mg/kg every 0.5 half-life during all waking hours. A 24-hour Holter test was recorded, beginning just prior to the second caffeine dose. It was concluded that in normal adults, even high-dose caffeine does not affect prevailing cardiac rhythm and rate, and moreover, does not cause clinically significant ventricular or supraventricular dysrhythm.

Adult↗
PubMed1987

Depression of murine hepatic mixed function oxidase during infection with Listeria monocytogenes.

The level of cytochrome P-450 and the oxidation of aminopyrine and benzo(a)pyrene hydroxylase were depressed in hepatic microsomes prepared from mice infected with the gram positive bacteria Listeria monocytogenes. Maximum depression of mixed function oxidase occurred on the 2nd day of infection. This loss in drug biotransformation capacity in the liver was correlated directly with the number of organisms found in that organ. The ability of mice to metabolize drugs in vivo also was impaired during Listeria monocytogenes infection. During the infective period the half-life of theophylline was significantly prolonged and the N-demethylation of aminopyrine as measured by the expiration of 14CO2 from radiolabeled aminopyrine was diminished. The loss of drug metabolism was not due to interferon production, fever or morphological damage to the liver. These results indicate that certain bacterial infections can depress drug biotransformation and elimination in a similar manner to that already reported in viral and parasitic infections. This finding may be of significance to patients receiving drugs which are metabolized by the mixed function oxidase system during episodes of infection with some bacteria.

Aminopyrine N-Demethylase↗
PubMed1986

Kupffer cell factor mediated depression of hepatic parenchymal cell cytochrome P-450.

Following the administration of latex particles (0.46 micron), cytochrome P-450 dependent monooxygenase system was depressed in the livers of mice. These particles were taken up exclusively by Kupffer cells in the liver, and no particles were found in the hepatocytes which contain most of the monooxygenase capacity in that organ. Cytochrome P-450 was also depressed in isolated hepatocytes incubated with phagocytosing Kupffer cells or the cell free filtrate from an incubation mixture of Kupffer cells and latex particles. Kupffer cells and hepatocytes were then incubated in a double-chambered vessel in which the two cell types were separated by a semi-permeable membrane. When latex particles were added to the chamber containing Kupffer cells, a factor was released which crossed the semi-permeable membrane and depressed cytochrome P-450 and benzo[a]pyrene hydroxylase in hepatocytes contained in the other chamber. It is concluded that, during the process of phagocytosis (in vivo or in vitro) by Kupffer cells in the liver, the levels of cytochrome P-450 and related drug biotransformation were depressed in the adjacent parenchymal cells.

Animals↗
PubMed1986

The role of lymphocytes, macrophages and interferon in the depression of drug metabolism by dextran sulfate.

Cytochrome P-450-mediated drug biotransformation is depressed by many immune stimulants. We have shown that such depression caused by the immune stimulant dextran sulfate is mediated by Kupffer cells. The purpose of this study is to determine if other cells of the immune system or a cellular product such as interferon are involved in the depressive action of dextran sulfate on drug metabolism. Plasma samples taken from mice treated with dextran sulfate contained no detectable interferon, yet hepatic cytochrome P-450 was significantly depressed, suggesting that interferon did not mediate the depression of drug metabolism by dextran sulfate. Administration of cyclophosphamide or antilymphocyte serum to mice prior to dextran sulfate to markedly decrease lymphocyte populations did not prevent the depressive actions of dextran sulfate on cytochrome P-450, suggesting that the lymphocyte population was not involved in the dextran sulfate mediated depression. Preincubation of dextran sulfate with peritoneal macrophages prior to incubation with hepatocytes significantly depressed hepatocyte cytochrome P-450 content, while dextran sulfate alone had no direct effect on hepatocyte cytochrome P-450 content. These results further support the hypothesis that macrophages play a major role in the depression of cytochrome P-450 by dextran sulfate.

Adjuvants, Immunologic↗
PubMed1979

Cytochrome P-450 and hepatic drug biotransformation during progressive cardiac disease in cardiomyopathic hamsters.

Reductions in cytochrome P-450 levels and aminopyrine N-demethylase activity of hepatic microsomes obtained from cardiomyopathic hamsters (BIO 14.6) occurred at all stages of the disease before the development of congestive heart failure (CHF). Cytochrome b5 levels were reduced only in animals with CHF when compared with age-matched controls (BIO.RB). Total microsomal protein and p-nitrophenol glucuronidation were not affected by the disease process. We conclude that the reduction in cytochrome P-450 levels and N-demethylase activity in cardiomyopathic hamsters is not a consequence of CHF, but is one of the manifestations of the disease process.

Aging↗
PubMed1979

The deleterious effect of Bordetella pertussis vaccine and poly(rI.rC) on the metabolism and disposition of phenytoin.

The elimination of phenytoin from blood was significantly decreased in rats pretreated 24 hr previously with Bordetella pertussis vaccine or the synthetic polynucleotide poly(rI.rC.). Phenytoin half-life was increased about 4-fold by both agents. In microsomes prepared from rats pretreated with B. pertussis vaccine or poly(rI.rC) the hydroxylation of phenytoin in vitro was decreased by 36 nad 53%, respectively. The addition of these agents to normal microsomal suspensions had no effect on phenytoin hydroxylation, demonstrating that the decrease in biotransformation was not due to direct enzyme inhibition. The decrease in phenytoin hydroxylation and elimination rate resulted from depressed levels of cytochrome P-450 in the hepatic endoplasmic reticulum of rats treated with B. pertussis vaccine or poly(rI.rC).

Animals↗
PubMed1976

NADPH-dependent lipid peroxidation and its effects on aminopyrine N-demethylation in subcellular fractions of human neonatal liver.

NADPH-dependent lipid peroxidation was determined in humans, using subcellular fractions of livers obtained from newborn infants. As reported for other species, activity was concentrated in the microsomal fraction and was similar to that found in the rat. High activity of lipid peroxidation induced by iron decreased aminopyrine N-demethylation and slightly reduced linearity time for the reaction. Compared with the rat, however, human microsomes were more resistant to the effects of lipid peroxidation. If liped peroxidation occurs in vivo it is unlikely to affect drug oxidation to any great degree in human infants.

Aminopyrine N-Demethylase↗
PubMed1975

Alterations of hepatic microsomal drug metabolism by glucagon.

The effect of glucagon on the components of the hepatic microsomal electron transport chain (NADPH oxidase, NADPH cytochrome c reductase (EC 1.6.2.4), cytochrome P-450, and NADPH cytochrome P-450 reductase), and on two representative oxidative pathways (aminopyrine N-demethylation, a type I substrate oxidation; and aniline p-hydroxylation, a type II substrate oxidation) was determined. Microsomes from rats pretreated with glucagon (300 mug/kg per day for 3 days) showed a significant decrease in NADPH oxidation and in aminopyrine N-demethylation with a prolonged hexobarbital sleeping time, and a significant increase in aniline p-hydroxylation. Microsomes from rats pretreated with a lower dose of glucagon (30 mug/kg per day for 3 days) showed a significant decrease in the microsomal N-demethylation of aminopyrine. Glucagon had no effect when added in vitro to microsomes, suggesting that the in vivo effects of glucagon are mediated indirectly in the intact animal.

Aminopyrine N-Demethylase↗