Coumarin is a naturally occurring compound that is used as a flavoring agent and
ID: 117343 • Letter: C
Question
Coumarin is a naturally occurring compound that is used as a flavoring agent and fragrance enhancer. It is hepatotoxic in a range of animals and has exhibited carcinogenicity in some studies. It is argued that because the metabolism of coumarin differs substantially between rodents and humans, exposure to coumarin does not pose a significant risk (Lake (1999) Food and Chemical Toxicology 37: 423- 453). Would the differences in metabolism be sufficient to adequately protect sensitive humans? Outline the metabolism of coumarin in humans and rodents, and explain the reasoning for your answer.Explanation / Answer
Yes, the differences in metabolism of humans and rodents are sufficient to protect sensitive humans. Humans can resist coumarin.
The maximum daily human exposure to coumarin from dietary sources for a 60-kg consumer has been estimated to be 0.02 mg/kg/day. From fragrance use in cosmetic products, coumarin exposure has been estimated to be 0.04 mg/kg/day. The total daily human exposure from dietary sources together with fragrance use in cosmetic products is thus 0.06 mg/kg/day.
No adverse effects of coumarin have been reported in susceptible species in response to doses which are more than 100 times the maximum human daily intake. The mechanism of coumarin-induced tumour formation in rodents is associated with metabolism-mediated, toxicity and it is concluded that exposure to coumarin from food and/or cosmetic products poses no health risk to humans.
Metabolism of coumarin in humans and rodents:
-In liver slices from all five species 7-ethoxycoumarin was metabolized to 7-hydroxycoumarin (7-HC), which was extensively conjugated with D-glucuronic acid and sulphate. In rat and mouse, 7-HC was preferentially conjugated with sulphate.
-Coumarin was metabolized by liver slices from all five species to various polar products and to metabolite(s) that bound covalently to liver slice proteins. In Cynomolgus monkey and both human subjects studied, 7-HC was the major metabolite that was conjugated with D-glucuronic acid and sulphate, whereas in rat the major metabolites were products of the 3-hydroxylation pathway and unknown metabolites. Major metabolites in mouse liver slices were 7-HC, 3-hydroxylation pathway products and unknown metabolites, and in guinea pig liver slices, 7-HC and unknown metabolites.
-The metabolism of 7-ethoxycoumarin to free and conjugated 7-HC and [3-14C]coumarin to total polar products was greater in liver slices from mouse and Cynomolgus monkey than the other three species.
-With liver slices from all five species there appeared to be little difference in the extent of metabolism of 7-ethoxycoumarin and [3-14C]coumarin to various products in either a complex tissue culture medium (RPMI 1640 plus foetal calf serum) or a simple balanced salt solution (Earle's balanced salt solution).
-These results demonstrate that precision-cut liver slices are a valuable in vitro model system for investigating species differences in xenobiotic metabolism.