Coumarin hydroxylation

The same effect has been reported for the coumarins hydroxylated at C- 7 and/or C- 8 positions [260]. Namely, the 3-carboxylic acids and ester derivatives (55b,c) were less active than their 3-unsubstituted congeners umbelliferone and daphnetin (55a,d) against phytopathogenic fungi. Acetylation of the hydroxyl groups generally increased the activity, probably due to the increase in lipophilic characteristics of these compounds. 

The distributions of phenolic isomers in hydroxylations in the animal body arc often similar to those obtained by Fenton s reagent. For example, the hydroxylation of coumarin by the rabbit gives the six hydroxycoumarins in amounts decreasing in the order 3- >7->6- >8- >4- /—5-, whereas Fenton s reagent gives mainly the 3-, 5-, and 7-derivatives with traces of the 6- and 8-derivatives. It may, however, be misleading to draw conclusions about the nature of... 

Chen, H. and Walsh, C.T. (2001) Coumarin formation in novobiocin biosynthesis beta-hydroxylation of the aminoacyl enzyme tyrosyl-S-NovH by a cytochrome P450 Novi. Chemistry Biology, 8, 301-312. 

Mouse CYP2A5 is a comparable isoform to human CYP2A6 (Raunio et al. 1988), because these isozymes are responsible for the majority of nicotine s C-oxidation (Raunio et al. 2008), cotinine s subsequent oxidation to 3 -hydroxycotinine (Sin and Tyndale 2007), and coumarin 7-hydroxylation (Kaipainen et al. 1984). Taken together, these findings suggest that mice may be a cost-effective animal model of human CYP2A6-mediated nicotine C-oxidation. 

Yamano S, Tatsuno J, Gonzalez FJ (1990) The CYP2A3 gene product catalyzes coumarin 7-hydroxylation in human liver microsomes. Biochemistry 29 1322-1329... 

Hydroxylated coumarins are present in grass and contribute to the smell of newly cut hay others have pharmaceutical and rodenticidal activities. The compound warfarin (5.2) was developed to kill rats, but is now often used as a blood anti-coagulant in human patients. 

Taguchi, G. et al., Cloning and characterization of a glucosyltransferase that reacts on 7-hydroxyl group of fiavonol and 3-hydroxyl group of coumarin from tobacco cells. Arch. Biochem. Biophys., 420, 95, 2003. 

The major pathway of coumarin metabolism in most human subjects is 7-hydroxyl-ation to form 7-hydroxy coumarin, which is excreted in the urine as both glucuronic acid and sulfate conjugates. Coumarin 7-hydroxylation activity exhibits a Gaussian distribution in Caucasian populations (Cholerton et al, 1992 Rautio et al, 1992), but some individuals are deficient in this activity. 

CYP2A6 (cytochrome P450 2A6) has been purified from human liver and CYP2A6 cDNA expression systems are available. Many studies have demonstrated marked interindividual variation in the levels of hepatic CYP2A6 protein, mRNA and associated microsomal coumarin 7-hydroxylase activity (reviewed in Pelkonen et al., 1997 Lake, 1999). The role of CYP2A6 in the metabolism of coumarin by human liver microsomes has been confirmed by Sai et al. (1999), who found that a monoclonal antibody to CYP2A6 inhibited coumarin 7-hydroxylation by more than 94%. 

While 7-hydroxylation is the major metabolic pathway of coumarin in most subjects, humans also convert coumarin to ort/io-hydroxyphenylacetic acid. 

Unlike in humans, the major metabolic pathway of coumarin in rats is the 3,4-epoxidation pathway. After a 100-mg/kg bw oral dose of [3- C]coumarin, urinary 3-hydroxycoumarin, 7-hydroxycoumarin, ort/zo-hydroxyphenyllactic acid and ortho-hydroxyphenylacetic acid accounted for 1.8, 0.4, 0.8 and 20% of the dose, respectively. Various metabolites including ort/zo-hydroxyphenylacetic acid were detected in the faeces (Kaighen Williams, 1961). Other studies in vivo have confirmed that rats are poor 7-hydroxylators of coumarin, with urinary 7-hydroxycoumarin accounting for < 1% of the dose (van Sumere Teuchy, 1971 Lake et al, 1989a). 

Because of the relative ease of measurement of 7-hydroxycoumarin, many studies have examined this pathway of coumarin metabolism after oral administration. Overall, several species including rats, most mouse strains, Syrian hamsters, guinea-pigs, dogs, marmosets and squirrel monkeys are poor 7-hydroxylators, excreting <5% of the administered dose as urinary 7-hydroxycoumarin (Cohen, 1979 Lake, 1999). 

Certain mouse strains, such as DBA/2 and 129/Rr strains, excrete up to 26% of an intra-peritoneally administered dose of coumarin as 7-hydroxycoumarin (Lush Andrews, 1978). Species such as rabbits, cats and pigs have been reported to excrete 12-19% of the dose as urinary 7-hydroxycoumarin (Kaighen Williams, 1961 Gangolli et ah, 1974 Lake, 1999). In contrast, baboons, like humans, are extensive 7-hydroxylators of coumarin, excreting 60-66% of a dose of coumarin as urinary 7-hydroxycoumarin (Gangolli eta/., 1974 Waller Chasseaud, 1981). 

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... 

Coumarin is rapidly and extensively absorbed after topical or oral administration to human subjects. It undergoes very extensive metabolism along two major pathways, 7-hydroxylation and ring-opening to ort/ro-hydroxyphenylacetaldehyde. There are numerous minor metabolites, many of which are secondary products from the primary metabolites. The relative extent of these two major pathways is highly variable between species. Ring-opening predominates in rodents, while 7-hydroxylation is particularly evident in htrmans. 

This is a large group of structurally diverse naturally occurring compounds that possess at least a phenolic moiety in their structures. Eor example, umbelliferone, a coumarin, has a phenolic hydroxyl functionality at C-7 quercetin is a flavonoid that has four phenolic hydroxyls at C-5, C-7, C-3 and C-4. Although the phenolic group of compounds encompasses various... 

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