Biotransformation of scoparone used to monitor changes in cytochrome P450 activities in primary hepatocyte cultures derived from rats, hamsters and monkeys.

The coumarin derivative scoparone is regioselectively demethylated yielding isoscopoletin and scopoletin. The ratio of the formation rates of these two metabolites (isoscopoletin/scopoletin; I/S ratio) is reported to mirror the contribution of several cytochrome P450 (P450) isoenzymes to the biotransformation of scoparine. The metabolism of scoparine has been studied in primary liver cell cultures of rats, hamsters, cynomolgus monkeys and in human liver cells. Rat hepatocytes appeared to metabolize scoparone 7 to 10 times slower than those of hamsters and monkeys. In hepatocyte monolayers of all three species the loss of P450 was paralleled by a decrease in total scoparone metabolism. In hamsters but not in rats, a decrease of the I/S ratio was found during primary culture of liver cells. A similar shift in the metabolic pattern of scoparine observed with the monkey hepatocytes was statistically not significant. Most likely, in hamster and possibly in monkey hepatocyte cultures the different P450s involved in scoparone metabolism decrease at unequal rates. In rat liver cells, however, the pattern of these P450 isoenzymes remains more or less unaltered. In contrast to liver cells from the other species, human hepatocytes did not secrete scopoletin in detectable amounts. Scoparone demethylation in humans may be qualitatively different from that in other mammals.