Coumarins hepatotoxicity

P-naphthoflavone or Aroclor 1254 did not significantly alter coumarin hepatotoxicity in C3H/He mice, while hepatic microsome metabolism of [ C]coumarin doubled following administration of either inducer. In DBA/2 mice, pretreatment with either P-naphthoflavone or Aroclor 1254 did not affect coumarin-induced hepatotoxicity. 

Casley-Smith, J.R. Casley-Smith, J.R. (1995) frequency of coumarin hepatotoxicity. Med. J.Aust., 162, 391... 

Cottrell, S., Oliver, K., Lake, B.G. Powell, C.J. (1996) Strain-specific enhancement or inhibition of coumarin hepatotoxicity in mice following pretreatment with two different liver enzyme-inducing agents. Fundam. appl. Toxicol, 34, 47-55 Cox, D., O Kennedy, R. Thornes, R.D. (1989) The rarity of liver toxicity inpatients treated with coumarin (1,2-benzopyrone). Hum. exp. Toxicol, 8, 501-506 Dexeus, E.H., Logothetis, C.J., Sella, A., Fitz, K., Amato, R., Reuben, J.M. Dozier, N. (1990) Phase II study of coumarin and cimetidine in patients with metastatic renal cell carcinoma. J. din. Oncol, 8, 325-329... 

Some cases of hepatotoxicity have been reported to be associated with exposure to coumarin. One possible case was reported by Beinssen (1994) and six by Loprinzi et al. (1997). Marshall et al. (1994) reported one case in which elevated serum aminotransferase levels were measured in a patient given 5 g coumarin per day. In two lymphoedema patients given 90 mg coumarin per day for five months, Koch et al. (1997) reported elevated serum alanine aminotransferase activity. Faurschou (1982) reported a case of toxic hepatitis in a patient given coumarin daily for eight weeks, which was characterized by hepatomegaly and elevated serum enzyme levels. All signs of liver toxicity returned to normal on cessation of treatment. 

Cottrell et al. (1996) reported that a single oral dose of coumarin produced liver necrosis in mice 200 mg/kg bw coumarin was hepatotoxic to both C3H/He and DBA/2 mice. Hepatotoxicity was characterized by an increase in plasma aminotransferase activity, mild subcapsular linear hepatocyte necrosis and, in some C3H/He mice, centrilobular necrosis. Mice were pretreated with (3-naphthoflavone (80 mg/kg bw), Aroclor 1254 (54, 125 or 162 mg/kg bw) or vehicle alone by intraperitoneal injection for three consecutive days. Twenty-four hours later, a single dose of coumarin (200 mg/kg bw) or vehicle was administered by gavage. Pretreatment with... 

In one-, four- and 13-week studies, the effects of coumarin treatment were compared in male Sprague-Dawley rats, CD-I mice and Syrian hamsters. Rats were fed 0-0.75% coumarin for one and four weeks and 0.5% coumarin for 13 weeks. Mice and hamsters were fed 0-0.5 and 0-1.0% coumarin, respectively, for one, four or 13 weeks. In the rat, coumarin caused dose-related hepatotoxic effects which included vacuolar degeneration, apoptosis and bile duct proliferation and increases in serum bilirubin content and both serum and hepatic y-glutamyltranspeptidase activity. A sustained stimulation of hepatocyte replicative DNA synthesis was observed in rats treated for four and 13 weeks. Levels of total hepatic glutathione were increased approximately twofold, and there were statistically significant decreases in microsomal cytochrome P450 content and ethylmorphine 7V-demethylase activity. These effects were reduced or not observed in mice and hamsters (Lake Grasso, 1996). 

Coumarin was administered in the diet for two years to Sprague-Dawley rats and CD-I mice in a study by Carlton et al. (1996) which is described more fiilly in Section 3.1.2. Histopaihological evidence of hepatotoxicity was observed in rats, with males affected more severely than females. No dose-related clinical signs were observed in the CD-I mice nor were there any changes in clinical pathology, haematology or microscopic pathology (Carlton et al, 1996). 

Ratanasavanh et al. (1996) prepared hepatocytes from male Sprague-Dawley rats, DBA/2J mice, Fauve de Bourgogne rabbits and humans. The hepatocytes were incubated with 0.1, 0.25 or 0.5 mmol/L coumarin (and 1 mmol/L for human hepatocytes). Coumarin was hepatotoxic in cells prepared from rats, mice and rabbits, as judged by cell morphology and by lactate dehydrogenase release. Human hepatocytes were sensitive to coumarin toxicity only at a concentration of 1 mmol/L. 

Marked inter-species differences have been observed in the metabolism and toxicity of coumarin. The metabolism of coumarin involves two primary pathways, 7-hydroxylation and ring-opening to ort/zo-hydrox5 henylacetaldehyde. Coumarin is hepatotoxic in rat, mouse and dog, species in which ring-opening predominates. In contrast, humans and baboons, in which 7-hydroxylation is most evident, rarely show... 

In humans exposed to coumarin for treatment of various clinical conditions, a few cases of hepatotoxicity have been reported. However, a clear relationship between the... 

Cholerton, S., Idle, M E., Vas, A., Gonzalez, F.J. Idle, J.R. (1992) Comparison of a novel thin-layer chromatographic-fluorescence detection method with a spectrofluorimetric method for the determination of 7-hydroxycoumarin in human urine. J. Chromatogr., 575, 325-330 Cohen, A.J. (1979) Critical review of the toxicology of coumarin with special reference to interspecies differences in metabolism and hepatotoxic response and their significance to man. Food chem. Toxicol, 17, 277-289... 

Fentem, J.H. Fry, J.R. (1993) Species differences in the metabolism and hepatotoxicity of conmarin. Comp. Biochem. Physiol, 104C, 1-8 Fentem, J.H., Fry, J.R. Whiting, D.A. (1991) o-Hydroxyphenylacetaldehyde a major novel metabolite of coumarin formed by rat, geibil and human liver microsomes. Biochem. Biophys. Res. Commun., 179, 197-203... 

Gallicchio, V.S., Hulette, B.C., Harmon, C. Marshall, M.E. (1989) Toxicity of coumarin (1,2-benzopyrone) on human peripheral blood mononuclear cells and human and murine bone marrow progenitor stem cells. J. biol. Res. Modifiers, 8, 116-121 Gangolh, S.D., Shilling, W.H., Grasso, P. Gaunt, I F. (1974) Studies on the metabolism and hepatotoxicity of coumarin in the baboon. Biochem. Soc. Transact., 2, 310-312... 

Lake, B.G. (1984) Investigations into the mechanism of coumarin-induced hepatotoxicity in... 

Lake, B.G (1999) Coumarin metabolism, toxicity and carcinogencity relevance for human risk assessment. Food chem. Toxicol., 37, 423 53 Lake, B.G Evans, J.G (1993) Effect of pretreatment with some mixed-function oxidase enzyme inducers on the acute hepatotoxicity of coumarin in the rat. Food chem. Toxicol., 31, 963-970... 

Lake, B.G Grasso, P. (1996) Comparison of the hepatotoxicity of coumarin in the raf mouse, and Syrian hamster a dose and time response study. Fundam. appl. Toxicol., 34, 105-117 Lake, B.G, Walters, D.G Gangolli, S.D. (1989a) Comparison of the metabohsm and disposition of [3- " C]coumarin in the rat and marmoset (Callithrix jacchus). Toxicol. Lett., 45, 299-306... 

Loprinzi, C.L., Sloan, J. Kugler, J. (1997) Coumarin-induced hepatotoxicity (Letter to the Editor). J. din. Oncol, 15, 3167-3168... 

Coumarin has hepatotoxic potential in man, when taken in daily doses of 25-100 mg (1). Bile-duct carcinomas have been reported to occnr in rats fed coumarin, but the correctness of this diagnosis has been seriously criticized. 

In rats and many strains of mice other than the DBA/2J, oral coumarin exposure results in hepatic metabolism of coumarin, with the formation of the coumarin 3,4-epoxide (CE), which spontaneously rearranges extremely rapidly to the o-hydroxyacet-aldehyde (o-HPA), the toxic metabolite. The o-HPA is then further metabolized to the nontoxic o-hydro-xyacetic acid (o-HPAA) and o-hydroxyethanol (o-HPE). Rodents also metabolize coumarin by several lesser pathways, to the nontoxic 3-hydroxycoumarin and several other more minor metabolites. It is the balance between the formation of the toxic o-HPA and the nontoxic o-HPAA and o-HPE that is critical to the determination of hepatotoxicity at high exposure levels of coumarin. Mice form more o-HPA than do rats, but detoxify it much more rapidly and efficiently than do rats. The result is that hepatotoxicity at doses 150 mg coumarin kg body weight is observed in rats, but not mice. Similarly, when high doses of coumarin result in high plasma levels, mice demonstrate pulmonary toxicity whereas rats do not. This is the result of the formation of higher levels of CE and o-EIPA in the Clara cells in the lungs of mice, which is not observed in rats. 

In contrast to the hepatotoxic action of coumarin, 4-methylcoumarin triggered off a protective mechanism by increasing microsomal protein synthesis. The... 

Many plant phenolics are of pharmaceutical interest. Flavonoids, lignans, flavolignans, coumarins, phenyl pro-panoids, and other phenolic compounds show a wide variety of biological and pharmacological activities, such as anti-oxidant, anti-hepatotoxic, spasmolytic, cytotoxic, anti-fungal, and anti-bacterial. Some flavonoids improve capillary resistance while isoflavonoids found in soy and other legumes have estrogenic activity. 

Centrilobular hepatic necrosis by single doses of coumarin (1,2-benzopyrone, ds-o-coumarinic acid lactone) have been reported in the rat (Lake 1984, Lake et al. 1989, Fentem et al. 1992), whereas chronic administration resulted in bile duct lesions (Hagan etal. 1967, Cohen 1979, Evans etal. 1989). The mechanism of acute coumarin-induced hepatotoxicity in the rat has been investigated by comparing the effects of coumarin with those of a number of methyl-substituted coumarin derivatives (Lake etal. 1994). Coumarin administration produced dose-related hepatic necrosis and a marked elevation of plasma alanine aminotransferase and aspartate aminotransferase activities. In contrast, non of the coumarin derivatives examined produced either hepatic necrosis or elevated plasma transaminase activities. Coumarin reduced hepatic microsomal ethylmorphine N-demethylase and 7-ethoxycoumarin 0-deethylase activities, whereas one or both mixed function oxidases appeared to be induced by treatment with 3,4-dimethylcoumarin, 4-methylcoumarin, 3-methyloctahydrocoumarin and 4-methyloctahydrocoumarin. These results provides an evidence that acute coumarin-induced hepatotoxicity in the rat is due to the formation of a coumarin 3,4-epoxide intermediate. 

---