Coumarins are lactones of o-hydroxycinnamic acid with aromatic odor. The parent nucleus structure of this class of compounds has three types of simple coumarins, furanocoumarins and pyranocoumarins, which are an important class of active ingredients in raw medicine, mainly distributed in plants of Umbelliferae, Leguminosae, Asteraceae, Rutaceae, Solanaceae, Rhynchophyceae and Orchidaceae. For example, psoralen lactone (psolalen) has photosensitizing activity and is used in the treatment of leukoplakia. Osthole is a coumarin-like active ingredient derived from Serpentine and Radix Angelicae Sinensis with pharmacological activity of inhibiting hepatitis B surface antigen (HBsAg). Begonia lactone (calophylloide) has strong anticoagulant effect. Artemisia hamartica lactone (scoparon) is the main active ingredient in the raw medicine Artemisia inchi to calm the liver and relax smooth muscle.
After entering the body, coumarins are easily absorbed and metabolized by cytochrome P450 catalysis. The metabolism of coumarins requires the participation of a large number of biological enzymes, and the metabolic pathways are mainly hydroxylation, dehydrogenation, demethylation, ring opening of lactone rings, and binding reactions, which finally produce a variety of compounds.
1. Oxidative metabolism
Oxidation reaction is a common drug metabolism reaction, including hydroxylation and dehydrogenation, among which hydroxylation reaction is the most common. Coumarins are easily hydroxylated by CYP2A6, and the hydroxylated coumarins are easily bound to glucuronic acid and sulfuric acid, and finally excreted in the form of conjugates through the kidneys. The 8-methylpsoralenolide in angelica is hydroxylated to produce 5-hydroxy-8-methoxypsoralenolide.
Demethylation is an important pathway of coumarin metabolism. After oral administration of 6,7-dimethoxycoumarin to rats, there are mainly 2 metabolites (M1 and M2) in the body. The analysis revealed that M1 and M2 are isomers of each other, which are sulfate esters conjugated with sulfuric acid molecules after the hydrolysis of 6,7-dimethoxycoumarin by demethylation to form 6-hydroxy-7-methoxycoumarin. The coumarin component of angelica, 8-methoxypsoralenolide, can be demethylated in vivo to produce the metabolite 8-hydroxysoralenolide. Methoxyparaffin can also undergo demethylation in liver microsomes to produce demethylmethoxyparaffin.
3. Binding metabolism
Coumarins contain one to more hydroxyl groups, which are easily combined with glucuronic acid, sulfuric acid and glutathione after hydroxylation in phase I metabolism (phase II metabolism), resulting in water-soluble compounds that are excreted from the body. The binding metabolism mainly occurs in the liver and intestine, and the epithelial cells of the small intestine mucosa have glucuronosyltransferase (UDPGT), sulfate transferase (ST), methyltransferase (MT) and other phase II metabolizing enzymes. Some coumarins are absorbed or metabolized by the intestine and continue to be metabolized after entering the liver from the portal vein. The binding metabolism of coumarins is mainly glucuronidation, sulfation, glutathione binding and methylation.
Coumarins are hepatotoxic to rats, but less so to mice. Rodents metabolize it primarily to 3,4-coumarin epoxide, a toxic, unstable compound, and further differential metabolism may lead to liver cancer in rats and lung tumors in mice.