Radioisomers of scoparone (6,7-dimethoxycoumarin) as a tool for in vivo differentiation of various hepatic monooxygenase inducers in mice using the breath test technique.
The oxidative removal of two different methyl groups from scoparone by a cytochrome P-450-mediated reaction proceeds with greater velocity for the 6-methyl group than for the 7-methyl group. In vivo experiments in mice were carried out with the two respective radioisomers [6-methyl-14C]scoparone and [7-methyl-14C]scoparone. The consecutive administration of the scoparone to the same animal is followed by collecting the 14CO2 exhaled (breath test). The maximal exhalation rate, measured 4 min after i.p. administration of the substrates, is four times greater for [6-methyl-14C]scoparone than for the [7-methyl-14C]scoparone. The total recovery of radioactivity in the whole animal (except skin) including the exhaled 14CO2 is 86% for [7-methyl-14C]scoparone and 84% for [6-methyl-14C]scoparone. Further analysis shows that the proportion of radioactivity found in various excretory routes is different; however, in the case of the poorly exhaled [7-methyl-14C]scoparone, almost twice as much radioactivity is found in bile and urine than for the more rapidly exhaled [6-methyl-14C]scoparone, whereas liver and other organs show little changes. Pretreatment of animals with various inducers, such as phenobarbital, 3-methylcholanthrene, warfarin and cobaltous chloride, characteristically affects the ratio of the two demethylations of scoparone. In the case of warfarin pretreatment, the ratio of the 6- to 7-demethylation is elevated to nearly 6, after cobaltous chloride the ratio is lowered to 2.8, whereas phenobarbital and 3-methylcholanthrene have no effect. These results may provide possibilities of noninvasive in vivo recognition of the inductive state of a pretreated animal.
D000818:Animals; D002245:Carbon Dioxide / Q000378:metabolism; D002250:Carbon Radioisotopes; D003374:Coumarins / Q000378:metabolism*; D003640:Dealkylation; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D008099:Liver / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010105:Oxygenases / Q000096:biosynthesis*; D012119:Respiration
C040637:6-methylscoparone; C040638:7-methylscoparone; D002250:Carbon Radioisotopes; D003374:Coumarins; D002245:Carbon Dioxide; D010105:Oxygenases; C018145:scoparone