EFFECT OF LICORICE AND GLYCYRRHIZIN ON MURINE LIVER CYP-DEPENDENT MONOOXYGENASES

This study is aimed to investigate the effect of the prolonged intake of conspicuous amounts of licorice (LE), or its natural constituent gl ycyrrhizin (G) on murine liver CYP-catalyzed drug metabolism. For this purpose the modulation of the regio-and stereo-selective hydroxylatio n of testosterone, together with the use of highly specific substrates as probes for different CYP isoforms such as ethoxyresorufin (CYP1A1) , methoxyresorufin (1A2), pentoxyresorufin (2B1), p-nitrophenol (2E1) and aminopyrine (3A), were investigated. Daily doses of licorice root extract (3,138 or 6,276 mg/kg b.w. per os), or G (240 or 480 mg/kg b.w . per os), were administered to different groups of Swiss Albino CD1 m ice of both sexes for 1, 4 or 10 consecutive days. While a single LE o r G dose was unable to affect the multienzymatic CYP-system, using bot h schedules of repeated treatment, either LE or G were able to signifi cantly induce hepatic CYP3A-and, to a lesser extent, 2B1-and 1A2-depen dent microsomal monooxygenase activities, as well as 6 beta-(mainly as sociated to CYP3A), 2 alpha-, 6 alpha-(CYP2A1, 2B1), 7 alpha-, 16 alph a-(CYP2B9) and 16 beta-testosterone hydroxylase (TH) activities in mal e and female mice. Data on CYP3A modulation, the major isoform present in human liver, was confirmed by using Western immunoblotting with an ti-CYP3A1/2 rabbit polyclonal antibodies raised against purified rat C YP3A. Northern blotting analysis using CYP3A cDNA biotinylated probe s howed that the expression of such isozyme is regulated at the mRNA lev el. These results suggest that the induction of cytochrome P450-depend ent activities by the prolonged intake of high LE or G doses, may resu lt in accelerated metabolism of coadministered drugs with important im plications for their disposition. The adverse effects associated with CYP changes such as toxicity/cotoxicity and comutagenicity may also ha ve clinical consequences.