Inter-species comparison of microsomal reductive transformation of biologically active benfluron N-oxide.
Benfluron N-oxide is an anti-neoplastic active metabolite of benfluron (B) /1/. It is generated by flavine-monooxygenase-catalysed reactions /2/ and immediately undergoes subsequent metabolic transformations, the most important of which are reductive reactions /3/. The products of reductive pathways catalysed by two different microsomal enzymatic systems are the tertiary amine benfluron (i.e. the original parent compound) and/or 7-dihydrobenfluron N-oxide. Our studies on the reductive transformation of B N-oxide in rat, mouse, guinea-pig, rabbit, mini-pig and human microsomes have revealed significant species differences both in the yields of respective reduced metabolites and in the conditions essential for the activity of the reductases involved. While B, the original tertiary amine, is the main product of aerobic incubation of B N-oxide with NADPH in rat, mouse and mini-pig, significantly higher activities of the enzymes catalysing the formation of 7-dihydro-B N-oxide have been detected in rabbit and human microsomes. In rat, mouse and mini-pig, NADPH rather than NADH is the preferred coenzyme for B formation, and NADPH is also the preferred coenzyme for the formation of 7-dihydro-B N-oxide in most of the species used. The yield of tertiary amine B is higher in anaerobic rather than aerobic conditions in most experimental species studied. Aerobic or anaerobic incubating conditions have an insignificant effect on the formation of 7-dihydro-B N-oxide. Based on the inhibitory effect of CO on the reductive transformation of B N-oxide, cytochromes P450 can be assumed to participate in the formation of B both in rat and mini-pig, and, in mini-pig only, also in the formation of 7-dihydro-B N-oxide. Inter-species comparison of the properties of the reductases participating in the transformation of B N-oxide shows that the rabbit is a suitable model to study reductive transformation of B N-oxide in man.
Skálová
L
L
Department of Biochemical Sciences, Faculty of Pharmacy, Charles University, Hradec Králové, Czech Republic.
Nobilis
M
M
Szotáková
B
B
Wsól
V
V
Kvasnicková
E
E
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D005449:Fluorenes / Q000493:pharmacokinetics*; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism*; D008954:Models, Biological; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase; D010084:Oxidation-Reduction; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D013552:Swine; D013556:Swine, Miniature
D000970:Antineoplastic Agents; D005449:Fluorenes; C034234:VUFB 13468; D009247:NADH, NADPH Oxidoreductases; D009251:NADPH-Ferrihemoprotein Reductase