Biomedical subjects

K W Renton

Publications and source records attributed to K W Renton.

At least 37 records · Page 2Linked to original sources

PubMed1994

Factors involved in the down-regulation of cytochrome P450 during Listeria monocytogenes infection.

The activation of host defense mechanisms has been shown to cause a depression in hepatic cytochrome P450-mediated metabolism in rodents and humans. In a previous study, it was demonstrated that the Gram-positive bacteria Listeria monocytogenes causes a down-regulation of hepatic cytochrome P450 and related substrate metabolism as a result of a pretranslational depression of apoprotein synthesis. The objectives of this study were to determine whether the effect of listeria on hepatocyte cytochrome P450 involves hepatic nonparenchymal cells and whether the hemolysin, secreted only by hemolytic forms of the bacteria, plays any part in mediating this effect. Total cytochrome P450 levels as well as ethoxyresorufin-O-dealkylase (EROD) and benzyloxyresorufin-O-dealkylase (BROD) activities were significantly reduced in hepatic microsomes isolated from mice infected in vivo for 48 h with 15U listeria, whereas the same dose of the avirulent non-hemolytic M3D strain had no effect. Listeria (15U) significantly depressed hepatocyte EROD and BROD activities after 24 h incubations with liver cell cultures containing hepatocytes and nonparenchymal cells, as the result of both a direct effect on the hepatocyte and an interaction of listeria with hepatic nonparenchymal cells. The M3D strain of listeria had no effect on cytochrome P-450-mediated metabolism in isolated cells, confirming that hemolysin is an essential component of the mechanism responsible for the down-regulation of cytochrome P450 during listeria infections.

Animals↗

PubMed1994

Acetylator phenotyping: the urinary caffeine metabolite ratio in slow acetylators correlates with a marker of systemic NAT1 activity.

Eighteen healthy Caucasians were evaluated for the systemic acetylation of a caffeine metabolite using the urinary caffeine metabolite ratio 5-acetylamino-6-formylamino-3-methyluracil (AFMU) to 1-methylaxanthine (1X) and for N-acetyltransferase activity in peripheral blood mononuclear leukocytes (MNL) using p-aminobenzoic acid (PABA). These are markers for systemic NAT2 and NAT1 N-acetyltransferase activities, respectively. Fourteen slow acetylators and four fast acetylators (the NAT2 polymorphism) were identified by the caffeine metabolite ratio. In slow acetylators who have decreased levels of hepatic NAT2, the AFMU/1X ratio was significantly correlated with PABA acetylation in MNL (r = 0.8; p = 0.0002). These results suggest that significant variation in the acetylation of arylamine substrates susceptible to the classical acetylator polymorphism is attributable to variation in NAT1 activity in the slow acetylator phenotype.

4-Aminobenzoic Acid↗

PubMed1994

Regulation of cytochrome P-4501A and cytochrome P-4502E induction in the rat during the production of interferon alpha/beta.

The down regulation of constitutive hepatic microsomal cytochromes P-450 (P450) by interferons has been well described in experimental animals and humans, however the down regulation of induced forms of P450 has not been documented clearly. Differential down regulation of constitutive and induced P450 could alter the proportions of P450 enzymes and, hence, the relative bioactivation/detoxification of xenobiotics. We investigated the effects of polyinosinic acid-polycytidylic acid, a potent stimulator of interferon alpha/beta production on CYP1A and CYP2E induction in the rat. Polyinosinic acid-polycytidylic acid down regulated the constitutive and pyridine-induced expression of CYP2E1 and the pyridine- and beta-naphthoflavone-induced expression of CYP1A1 as demonstrated by metabolic activity and immunoblot analyses. Depression of CYP2E1 and CYP1A1 protein expression by polyinosinic acid-polycytidylic acid was accompanied by a corresponding decrease in mRNA encoding these proteins. Induction of CYP1A2 mRNA also was depressed. Therefore, interferon alpha/beta down regulated induction of members of the CYP1A and CYP2E subfamilies at a pretranslational level independent of the mechanism of induction. Induction of the CYP1A and CYP2E subfamilies did not confer resistance to down regulation by interferon, although the magnitude of down regulation by interferon appeared to be influenced by the magnitude of P450 induction. The potential significance of down regulation of induced P450 in the clearance of certain therapeutic agents and in xenobiotic bioactivation and detoxification is discussed.

Animals↗

PubMed1993

Dissociation of xanthine oxidase induction and cytochrome P450 depression during interferon induction in the rat.

Interferon (IFN) and IFN inducers down-regulate hepatic cytochrome P450 (P450) through a pretranslational mechanism involving depression of P450 mRNA levels and a subsequent decrease in P450 synthesis. Current evidence suggests that interferon induces the synthesis of a protein which subsequently mediates the down-regulation of P450. Xanthine oxidase (XO) activity is induced by interferons in rodents, and the XO inhibitor allopurinol (AP) inhibits the down-regulation of P450 by interferons in the mouse and hamster so it has been proposed as the putative intermediate protein. In studies undertaken in rats to further characterize the molecular basis of the protective effect of AP, we observed that AP (20 and 50 mg/kg) did not protect against down-regulation of P450 by the interferon inducer polyinosinic-polycytidylic acid (10 mg/kg). In fact, at 50 mg/kg AP had an additive effect on the depression of CYP2E1. Total XO induction in the rat was only 30-50% compared with 100-500% in mice and hamsters, and this induction was inhibited completely by AP. Therefore, XO does not mediate the down-regulation of hepatic cytochrome P450 by interferons in the rat.

Allopurinol↗

PubMed1993

Modulatory effect of hyperthermia on hepatic microsomal cytochrome P450 in mice.

It is widely known that the clearance of drugs is often compromised during episodes of infectious disease via a down-regulation of cytochrome P450 (P450) at a pre-translational step in enzyme synthesis. Etiocholanolone (ETC), a potent inflammatory agent, induces fever in humans and causes a decrease in the clearance of certain drugs that are metabolized by P450. On this basis it is widely believed that the fever per se rather than the immune modulation that occurs during infections may have a major role in depression of microsomal P450 enzymes during viral infections in humans. In the present study, we demonstrated that although ETC did not induce hyperthermia in mice, it still evoked a depression of the levels of P450 in hepatic microsomes. Ethoxyresorufin O-deethylase (EROD) was also inhibited significantly when hepatic microsomes were incubated with various concentrations of ETC in vitro. P450 levels and EROD activities remained unchanged following hyperthermia that was induced by a non-inflammatory procedure using 2,4-dinitrophenol. Provided the response in rodents is similar to humans, these results indicate that the depression of drug biotransformation by ETC in humans is more likely to be caused by the direct effects of this agent or other mechanisms rather than by the fever it produces. This may suggest that the loss of drug metabolism in humans during infections is due to the activation of host defence responses rather than to the febrile nature of the illness.

2,4-Dinitrophenol↗

PubMed1993

Hepatic cytochrome P450 and related drug biotransformation during an outbreak of mouse hepatitis virus in a colony of Swiss BALB/c mice.

Mouse hepatitis is a common highly infectious virus of the Coronaviridae family that commonly infects laboratory colonies of BALB/c mice. In a natural outbreak of this disease in our institution we demonstrated that mouse hepatitis virus appears to have little or no effect on the levels of cytochrome P450 or on the activities of ethoxyresorufin O-dealkylase and benzyloxy resorufin O-dealkylase in hepatic microsomes. Antibody titers for the virus were elevated in all mice tested and were negative in a control uninfected group. In a number of studies carried out over a period of months during the active outbreak we did not observe lower levels of cytochrome P450 in comparison with infectious free periods. Although the activation of host defence mechanisms and infections are well known to diminish the cytochrome P450 enzyme system in the liver, these results indicate that during a period of confirmed active infection with mouse hepatitis virus there was no evidence of an impairment in drug biotransformation enzymes.

Animals↗

PubMed1993

Mechanism of hepatic cytochrome P450 modulation during Listeria monocytogenes infection in mice.

There have been numerous reports of altered drug clearance during episodes of viral infection and during the clinical use of recombinant interferons, but there have been very few reports regarding the effect of active bacterial infections on cytochrome P450-mediated metabolism. The objective of this study was to determine the mechanism by which the Gram-positive bacteria Listeria monocytogenes causes a depression of cytochrome P450-mediated biotransformation in mice. After induction with beta-napthoflavone, hepatic microsomal cytochrome P450 levels were reduced by 40% and ethoxyresorufin-O-dealkylase (EROD) activity was decreased by 65% in mice infected for 48 hr. The loss of EROD activity was accompanied by losses of cytochrome P450IA apoenzyme and cytochrome P450IA mRNA. Listeria infection did not affect total mRNA levels, as determined by oligo(dT)18 hybridization. The time course of these effects demonstrated that an up-regulation of cytochrome P450IA preceded the loss of this isozyme and that changes in cytochrome P450IA mRNA preceded the changes in apoenzyme levels and EROD activity. In hepatic microsomes from uninduced mice, cytochrome P450 levels and the rates of dealkylation of ethoxyresorufin, benzyloxyresorufin, pentoxyresorufin, and aminopyrine were significantly reduced, by 40-60%, after 48 hr of infection. The decrease in aminopyrine-N-demethylase activity was accompanied by a loss of cytochrome P450IID9 mRNA after 48 hr of infection. Cytochrome P450IID9 mRNA levels returned to normal after 96 hr of infection, whereas aminopyrine-N-demethylase activity was still decreased at this time. No up-regulation of cytochrome P450IID9 occured before the loss of this isozyme. The results of this study indicate that the changes in the levels of cytochrome P450IA and cytochrome P450IID9 that are observed during L. monocytogenes infection occur at a pretranslational step. If other bacteria have a similar capacity to depress cytochrome P450 by such a mechanism, then drugs with narrow therapeutic indices should be administered with caution during infectious diseases caused by bacteria or viruses.

Animals↗

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↗

PubMed1989

Induction and depression of cytochrome P-450-dependent mixed-function oxidase by a cloned consensus alpha-interferon (IFN-alpha CON1) in the hamster.

A novel analogue of human alpha-interferon (IFN-alpha CON1) was tested for its ability to modify the hepatic cytochrome P-450-dependent mixed-function oxidase system in the hamster. This cloned interferon was derived by selecting the most frequently observed amino acid sequences at each position in the known human alpha-interferon subtypes. IFN-alpha CON1 had a biphasic effect on cytochrome P-450 and related drug biotransformation in the hamster causing an initial increase followed by a significant depression. IFN-alpha CON1 also had a biphasic effect on cytochrome P-450 in the lung, adrenal and spleen but only a depressant effect in the kidney. This effect was not due to morphological damage and followed the species specificity for this type of interferon. Both the increase and the decrease in cytochrome P-450 could be prevented by the administration of the protein synthesis inhibitor puromycin. Various isozymes of cytochrome P-450 induced by phenobarbital, beta-napthaflavone and clofibrate were also depressed by this interferon. The results presented in this report suggest that IFN-alpha CON1 interferon will likely depress drug biotransformation in humans because the antiviral effects and the "anti-cytochrome P-450" effect of interferons cannot be separated, and this interferon has antiviral properties in both hamster and human cells. Clinically relevant drug interactions may be common during the concomitant use of this interferon and other drugs that are metabolized by cytochrome P-450.

Animals↗

PubMed1989

The interaction between carbamazepine and erythromycin.

Erythromycin has been reported to interact with the anticonvulsant, carbamazepine, in both children and adults. Toxic serum levels of carbamazepine are observed within 24 h of antibiotic administration, suggesting a mechanism not previously described for other erythromycin-based drug interactions. In rats erythromycin significantly depressed the elimination of carbamazepine in animals induced with carbamazepine for 4 days but had no effect on carbamazepine elimination in noninduced animals. Although the in vitro metabolism of carbamazepine to its epoxide by hepatic microsomes prepared from noninduced rats was significantly inhibited by erythromycin, the inhibition of carbamazepine epoxidation was greatly enhanced in carbamazepine-induced rats. In the pig the sensitivity of carbamazepine metabolism to erythromycin was much greater than in the rat, indicating the existence of a large species difference in this particular drug interaction. It is concluded that the interaction between erythromycin and carbamazepine is caused by a direct inhibition of carbamazepine oxidation by the antibiotic.

Animals↗

PubMed1988

Changes in serum anticonvulsant levels with febrile illness in children with epilepsy.

Changes in anticonvulsant serum levels during intercurrent illness may cause toxicity or decreased seizure control in children with epilepsy. We studied prospectively the effect of intercurrent illness and its treatment in 111 children being treated with AC monotherapy. Free fraction and total serum AC levels were determined when the child was well, on the fifth day of any illness with fever and one month after recovery. There were 55 episodes of febrile illness in 39 children during the study period. Twelve illnesses were associated with significant increases or decreases in serum AC levels; 7 children became clinically toxic; 1 child had increased seizures during illness. The mechanisms of AC level changes appeared to include interaction with antibiotics, with antipyretics or with viral illness. Amoxycillin and acetaminophen did not appear to interact with the AC's used. Physicians caring for children with epilepsy should be aware of the frequency and complexity of potential interactions between intercurrent febrile illness and anticonvulsant medication.

Adolescent↗

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↗