rutin and Liver-Diseases

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.. 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.. 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.. No evidence was obtained that the studied polymorphism in CYP2A6 is a determinant of the coumarin-associated liver dysfunction.

Topics: Adult; Aged; Anticoagulants; Aryl Hydrocarbon Hydroxylases; Chemical and Drug Induced Liver Injury; Coumarins; Cytochrome P-450 CYP2A6; Double-Blind Method; Drug Combinations; Female; Gene Frequency; Genotype; Humans; Hydroxyethylrutoside; Liver Diseases; Liver Function Tests; Male; Middle Aged; Mixed Function Oxygenases; Polymorphism, Genetic; Prospective Studies; Smoking; Venous Insufficiency

The results of the presented double-blind trial proved that the benzopyrone compound Venalot, a combination of coumarin and troxerutin used in the treatment of local inflammatory oedemas of traumetic, phlebopathic and lymphostatic origin, can be administered unhestitatingly in case of severe parenchymatous liver damages even in a dosage which was chosed higher than that recommended and usually given (2 depot tablets b.d.).

Topics: Adult; Aged; Coumarins; Drug Combinations; Edema; Female; Humans; Hydroxyethylrutoside; Liver; Liver Diseases; Liver Function Tests; Male; Middle Aged; Rutin

Both male and female Wistar rats were treated with daily oral doses of a combination of the active components coumarin and troxerutin (Venalot-Depot) corresponding to 1, 8, 64 and 128 mg coumarin/kg b.w., respectively. Goal of the study was to study coumarin at the target organ liver for a longer period, after it had turned out from a fertility and teratogenicity study that liver alterations were observed in the P-generation following the elevated doses' treatment up to 10 weeks (male) and 3 weeks (female). Light and electron microscopic examinations of the livers revealed the following findings: The lesions are dose- and time-dependent. First signs of coumarin-induced hepatocellular alterations are fine granular protein-like precipitations in the region of the sER (smooth endoplasmatic reticulum) which conflux to large areas. The glycogen content decreases significantly at the same time. This is followed by an osmotically controlled water redistribution in the cytoplasm and an increased water inflow from the extracellular space (vacuolar degeneration) as well as an overload of the cytoplasm with lipids, taken in by nutrition. Doses of 64 and 128 mg/kg b.w. of the test substance produced extensive hepatic alterations, associated with hypertrophy of the liver, with a focal onset in the globular periphery, subsequently extending to peripheral and intermediate lobular areas. Since light or electron microscopic alterations were not observed following doses of 1 and 8 mg/kg b.w., the dose of 8 mg coumarin/kg b.w. can be determined as no effect dose for the rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Chemical and Drug Induced Liver Injury; Coumarins; Dose-Response Relationship, Drug; Drug Combinations; Endoplasmic Reticulum; Female; Hydroxyethylrutoside; Hypertrophy; Liver; Liver Diseases; Male; Microscopy, Electron; Rats; Rats, Inbred Strains; Rutin; Time Factors