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W Legrum

Publications and source records attributed to W Legrum.

At least 19 recordsLinked to original sources
PubMed2003

Single copy of variant CYP2A6 alleles does not confer susceptibility to liver dysfunction in patients treated with coumarin.

OBJECTIVE: Coumarin, used in the treatment of chronic venous diseases, is mainly metabolized to non-toxic 7-hydroxy-coumarin by CYP2A6. At least, 3 variant alleles, CYP2A6*2, CYP2A6*3 and CYP2A6*4A, have been shown to encode catalytically defective proteins. Sporadic elevation of liver enzymes has been reported on the chronic administration ofcoumarin. We sought to determine if susceptibility to coumarin-associated liver dysfunction is genetically determined by polymorphism in CYP2A6 and impairment of the 7-hydroxylation ofcoumarin. Additionally, we were interested in the effect of polymorphism on smoking because of the predominant role of CYP2A6 in the metabolism of nicotine. METHODS: The investigation was performed prospectively within a randomized double-blind clinical trial of the coumarin-containing drug SB-LOT (90 mg coumarin + 540 mg troxerutin/d) vs. placebo in 231 German patients with chronic venous insufficiency. Monitoring of the hepatic status involved regular measurements of liver function during the 16-week treatment. Genotyping of CYP2A6 was carried out by means of PCR and confirmed by DNA sequencing analysis. RESULTS: The allelic frequencies of the variant CYP2A6*2 and CYP2A6*3 alleles were 0.023 and 0.014, respectively. There was no significant difference in the incidence of liver dysfunction between heterozygotes with CYP2A6*2, CYP2A6*3 and wild-type homozygotes. CYP2A6 polymorphism had no significant effect on smoking behavior. CONCLUSION: No evidence was obtained that the studied polymorphism in CYP2A6 is a determinant of the coumarin-associated liver dysfunction.

Adult↗
PubMed2000

Genetic polymorphism of CYP2A6 in the German population.

Genetic polymorphism of drug metabolizing enzymes (DME) can lead to severe toxicity or therapeutic failure of pharmacotherapy. Additionally, genetically determined differences in the activity of the metabolic enzymes can increase an individual's susceptibility to certain types of chemically induced cancers and possibly other diseases. Cytochrome P450 is one of the most important metabolic systems of the organism involved in the oxidation of different xenobiotics. This contribution summarizes and updates the information concerning the genetic polymorphism of the CYP2A6 isoform of the cytochrome P450. A special emphasis is put upon the genotyping techniques of CYP2A6 with a comparative analysis of their predictable sensitivity and specificity given on the example of the German population.

Aryl Hydrocarbon Hydroxylases↗
PubMed2000

A new method of capillary electrophoresis for metabolites of coumarin.

The metabolism of coumarin has been very widely investigated compared with other natural compounds. We know today that genetic variations lead to human groups with a high or low coumarin-metabolism. An effective capillary-electrophoresis method has been developed to study these effects on metabolic patterns. The seven most important metabolites can be analysed in one step. Therefore also small volume samples can be examined for phase-I-reactions (hydroxylation of coumarin) as well as for secondary reactions (e.g. glucuronidation or decomposition of the lactone-structure).

Animals↗
PubMed1999

Naringenin and interindividual variability in interaction of coumarin with grapefruit juice.

UNLABELLED: Grapefruit juice has been shown to enhance oral bioavailability of several drugs including coumarin. The degree of the interaction is highly variable among the individuals. OBJECTIVE: The aim of the study was to evaluate the interindividual variability in the pharmacokinetic profile of three components of grapefruit juice (naringin/naringenin, scopoletin, umbelliferone) and to compare it with the pattern of coumarin-grapefruit juice interaction. STUDY DESIGN: A two-set clinical study with the participation of 18 healthy volunteers was designed. In the first set of the experiment the total renal recovery of naringenin, scopoletin and umbelliferone within 13 hours after the intake of 1L grapefruit juice was estimated. Four individuals, who had demonstrated extremely high or extremely low excretion of the metabolites in the first set, were selected for the second set. The subjects took 10 mg coumarin with 1L grapefruit juice vs 10 mg coumarin with 1 L water in a cross-over manner. The interaction pattern was evaluated according to the time-course curves of 7-hydroxycoumarin (main metabolite of coumarin) excreted with urine. The detailed time-course excretory profiles of naringenin and scopoletin from grapefruit juice were also obtained. RESULTS: The screening demonstrated a significant interindividual variability in the renal excretion of naringenin (max/min > 15), scopoletin (max/min = 6.2), umbelliferone (max/min = 3.3). The interaction between coumarin and grapefruit juice has been observed by increase in the total recovery of 7-hydroxycoumarin up to 3 mg and by delay in time of its excretion by 2-3 hours. This interaction has been observed in 3 of 4 subjects and correlated with naringenin amounts in the urine. The mechanism and the sites of the interaction, as well as the causes for its wide interindividual variability are discussed in the paper.

Adult↗
PubMed1998

7-Aminocoumarins are substrates of cytochrome P450-isozymes.

N-Alkyl-7-aminocoumarins are dealkylated by murine cytochrome P450. There are differences between the N-dealkylation of secondary and tertiary amines. 7-Ethylamino-4-methylcoumarin is deethylated by isozymes induced by 3-methylcholanthrene, in contrast to 7-diethylamino-4-methylcoumarin and 7-diethyl-amino-4-trifluoromethylcoumarin, which are deethylated mostly by isozymes induced by phenobarbital. Although the deethylation of the secondary amine can be increased also by a pretreatment with pyrazole, a specific inducer of the coumarin 7-hydroxylase (CYP2A5), there is no specific affinity for this isozyme. This result is supported by the second specific inducer of CYP2A5 cobalt, because cobalt did not influence the deethylation of 7-ethylamino-4-methylcoumarin. In addition, it was shown that (in contrast to earlier investigations) pyrazole beside CYP2A5 also induces further cytochrome P450 isozymes. In series of four compounds, 7-ethylamino-4-methylcoumarin is the singular 7-aminocoumarin which is accepted as substrate by the coumarin 7-hydroxylase. In addition, the metabolism of the 7-aminocoumarins was investigated to look for further metabolic products. The most interesting result is the double deethylation of 7-diethylamino-4-methylcoumarin to the primary amine. In the scope of the studies the advantages of new calculating structure-activity-relationships (QSAR-plot) could also be demonstrated.

Animals↗
PubMed1997

The character of inhibition of the metabolism of 1,2-benzopyrone (coumarin) by grapefruit juice in human.

OBJECTIVE: Constituents of grapefruit juice are known to interfere with mammalian cytochrome P450 isozymes such as intestinal CYP3A4 and hepatic CYP2A6, lowering the biotransformation of drugs and increasing their bioavailability. The aim of this study was to investigate whether the presence of naringin is demanded for the inhibition of the coumarin 7-hydroxylase in man or other compounds are responsible for it. METHODS: In cross-over studies, doses of 10 mg coumarin, together with combinations of grapefruit juice, water and naringin, were given orally to one healthy male volunteer, We investigated increasing amounts of grapefruit juice, keeping the volume of liquid constant at 1 L; increasing doses of naringin given in water; increasing amounts of juice, keeping the dose of naringin constant; or increasing doses of naringin, keeping the amount of juice constant. Urine samples were collected up to 24 h after dosing and 7-hydroxycoumarin was quantified fluorimetrically in urine hydrolysates after HPLC separation to determine the excretion rates. RESULTS: While increasing amounts of grapefruit juice delay the excretion of 7-hydroxycoumarin by 2 h, increasing doses of naringin in water up to twofold (i.e. naringin content of 2 L grapefruit juice) do not cause any alteration in the time course of excretion. Experiments with increasing amounts of juice, keeping the dose of naringin constant, indicate that the inhibitory potency of small amounts of grapefruit juice can be amplified by naringin. The same is true when the ratio between juice constituents and naringin is enhanced up to threefold by adding naringin. CONCLUSION: As naringin alone is ineffective, the inhibitory effect of grapefruit juice on the metabolism of coumarin is caused by at least one compound other than naringin. The persistency of the primary inhibitor not identified yet can obviously be modulated by the naring(en)in-system.

Anticoagulants↗
PubMed1996

Inorganic tin -- a new selective inducer of the murine coumarin 7-hydroxylase (CYP2A5).

The coumarin 7-hydroxylase of mice (Coh, CYP2A5) is known to be highly selectively inducible by both a set of heavy metals such as cobalt, indium and cerium and a variety of organic nitrogen-containing heteroaromatic compounds such as 3-amino-1,2,4-triazole, pyrazine and pyrazole. The investigations presented reveal that inorganic divalent tin has to be included in the list of selective inducers. Pretreatment of NMRI-mice with 50 mg SnCl2/kg body weight, daily for 2 days, increases the coumarin hydroxylation 40- and 20-fold in the kidney and liver, respectively. So far, the inducing potency of tin chloride is higher than that of the agents already known. The diagnostic inhibitor metyrapone strongly inhibits the coumarin model reaction. In the kidneys tin generates an almost pure fraction of a cytochrome P450 isozyme catalyzing the metabolism of coumarins, as inhibition experiments reveal.

Animals↗
PubMed1996

Metabolic and analytical interactions of grapefruit juice and 1,2-benzopyrone (coumarin) in man.

OBJECTIVE: Grapefruit juice is known to inhibit mammalian cytochrome P450 isozymes such as CYP3A4. The aim of this study was to investigate the influence of the juice on the fate of coumarin (1,2-benzopyrone) metabolized by CYP2A6 in man. Its potentially inhibitory effect was examined when low and high amounts of grapefruit juice were taken. METHODS: In crossover studies, doses of 10 mg coumarin (Venalot) were given orally to an healthy male volunteer. The drug was taken either with water or with grapefruit juice, at different volumes (300 ml or 4 x 250 ml at intervals of 30 min). Urine samples were collected up to 24 h after dosing. After in vitro hydrolysis they were analysed fluorimetrically for umbelliferone, the metabolite of coumarin, and cumulative excretion curves were established. HPLC and TLC served to identify fluorescent metabolites from the juice. RESULTS: If coumarin is given in water its excretion is complete after 6 h and 70% of the dose is recovered. Grapefruit juice (300 ml) given simultaneously slightly retards the appearance of the fluorescent metabolite in the urine within the first few hours. The recovery of coumarin remains unaffected. One litre of juice enhances the delay and increases the recovery of coumarin to nearly 100%. Respective controls with grapefruit juice alone lead to remarkable excretions of a fluorescent material identified as conjugated scopoletin, which strongly interferes with the analysis of the coumarin experiment. The precursor of scopoletin is widely present at different concentrations in commercially available grapefruit juices. However, the autoinhibition of the juice is correlated neither to the concentration of naringin nor to that of scopoletin. CONCLUSION: Only grapefruit juice given at high doses (1 L) retards the appearance of the main metabolite of coumarin administered orally but increases its recovery. Due to scopoletin formed from the grapefruit juice, experiments especially with coumarin are strongly affected.

Anticoagulants↗
PubMed1994

[Dental alloys].

Explore the source record for details and available documents.

Chromium↗
PubMed1994

Approach to detect substrates suitable to measure the coumarin 7-hydroxylase (Cyp 2a-5)-structure-activity relationships.

Besides coumarin, which up to now has remained the most selective substrate for the coumarin 7-hydroxylase (Coh), 7-ethoxycoumarin, quinoline, 4-methylcoumarin, 7-ethoxy-4-methylcoumarin, 7-ethoxy-4-ethylcoumarin, and psoralen are suitable for this enzyme. The quantification of the suitability of a substrate to selectively measure the coumarin 7-hydroxylase is achieved by a graphic method. Requirements for serving as a substrate of the Coh are bicyclic ring systems with an electron rich moiety.

Animals↗
PubMed1992

Pharmacokinetic interaction between carbamazepine and neuroleptics after combined prolonged treatment in rats.

This study investigates how neuroleptics of phenothiazine or thioxanthene structure influence the pharmacokinetics of carbamazepine. Experiments were carried out on male Wistar rats. Carbamazepine and the neuroleptics were administered i.p., separately or together, for 2 weeks in the following daily doses (mg/kg): carbamazepine 15 during the 1st week of treatment and 20 during the 2nd week of treatment, promazine 10, chlorpromazine 2, perazine 10, chlorprothixene 2, flupenthixol 0.5. One hour after the last injection of carbamazepine and/or the neuroleptic, samples of blood plasma and brain were taken to determine the concentrations of carbamazepine and two of its metabolites: 10,11-epoxide and trans-10,11-diol. The neuroleptics increased the concentration of carbamazepine in plasma and in brain, but tended to decrease (with the exception of chlorpromazine) the concentration of the epoxide and increased the concentration of trans-10,11-diol. Metabolic in vitro studies did not show any significant differences between rats treated with carbamazepine alone and those treated with carbamazepine plus neuroleptic in the rates of the carbamazepine epoxidation, of 10,11-epoxide hydrolysis or of 1-naphthol glucuronidation.

Animals↗
PubMed1992

Effects of phenolic smoke condensates and their components on hepatic drug metabolizing systems.

Treatment of food with wood smoke is a long-established method of preservation and flavouring food. Recently, hardwood smoke condensates, purified of polycyclic hydrocarbons, have become of importance for direct flavouring of sausage-meat. The acute toxicity of the purified phenolic fraction in mice after intraperitoneal administration was therefore investigated. The LD50 was found to be 940 mg/kg body weight, which is about three times the LD50 of phenol (about 300 mg/kg). Only high concentrations of phenols or smoke condensate fractions are able to damage cytochrome P-450 by conversion to cytochrome P-420, whereas lower concentrations exhibit inhibitory effects on monooxygenase activity. Inductive properties of the phenolic fractions could not be demonstrated. Concentrations in vivo of free phenolic compounds do not reach inhibitory levels, since the hexobarbital-induced sleeping-time and 14CO2-exhalation after administration of p-[methoxy-14C] acetanilide are not altered. It is concluded that the phenolic compound intake with food regularly treated with smoke condensate fractions is below a toxicologically relevant level.

7-Alkoxycoumarin O-Dealkylase↗