7-Aminocoumarins are substrates of cytochrome P450-isozymes.
N-Alkyl-7-aminocoumarins are dealkylated by murine cytochrome P450. There are differences between the N-dealkylation of secondary and tertiary amines. 7-Ethylamino-4-methylcoumarin is deethylated by isozymes induced by 3-methylcholanthrene, in contrast to 7-diethylamino-4-methylcoumarin and 7-diethyl-amino-4-trifluoromethylcoumarin, which are deethylated mostly by isozymes induced by phenobarbital. Although the deethylation of the secondary amine can be increased also by a pretreatment with pyrazole, a specific inducer of the coumarin 7-hydroxylase (CYP2A5), there is no specific affinity for this isozyme. This result is supported by the second specific inducer of CYP2A5 cobalt, because cobalt did not influence the deethylation of 7-ethylamino-4-methylcoumarin. In addition, it was shown that (in contrast to earlier investigations) pyrazole beside CYP2A5 also induces further cytochrome P450 isozymes. In series of four compounds, 7-ethylamino-4-methylcoumarin is the singular 7-aminocoumarin which is accepted as substrate by the coumarin 7-hydroxylase. In addition, the metabolism of the 7-aminocoumarins was investigated to look for further metabolic products. The most interesting result is the double deethylation of 7-diethylamino-4-methylcoumarin to the primary amine. In the scope of the studies the advantages of new calculating structure-activity-relationships (QSAR-plot) could also be demonstrated.
Tegtmeier
M
M
University of Marburg, School of Medicine, Germany.
Legrum
W
W
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D003374:Coumarins / Q000737:chemistry*; D065637:Cytochrome P-450 CYP2A6; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D003374:Coumarins; D007527:Isoenzymes; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585520:Cyp2a5 protein, mouse; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2; C080488:7-aminocoumarin