Fibrates and their newly synthesized glycinate or glycinate-methylester derivatives: comparison of the interactions with liver cytochrome P450 dependent monooxygenase- and oxidase-functions in vitro.
Different fibrates (bezafibrate, ciprofibrate, clofibrate, fenofibrate, gemfibrozil) were investigated in comparison with their newly synthesized glycinate and glycinate-methylester derivatives. Interactions with the cytochrome P450 (CYP) system were studied by assessing binding to CYP and effects on CYP mediated monooxygenase functions in rat liver 9000 g supernatants, as measured by six model reactions for different CYP isoforms (ethoxyresorufin O-deethylation, ethoxycoumarin O-deethylation, pentoxyresorufin O-depentylation, p-nitrophenol-hydroxylation, ethylmorphine N-demethylation, lauric acid 11- or 12-hydroxylation). Possible prooxidant or antioxidant properties were investigated by the stimulated lipid peroxidation, hydrogen peroxide production, and lucigenin and luminol amplified chemiluminescence using rat liver microsomes. Additionally, the influence on luminol amplified rat whole blood chemiluminescence was examined. All substances tested displayed binding to CYP. Effects on the monooxygenase model reactions were in general more distinct with the glycinates than with the parent compounds and most pronounced with the glycinate-methylester derivatives. The slightest effects on all model reactions were seen with clofibrate and its derivatives. On the whole, low antioxidative rather than prooxidative effects were observed. In general and with most model reactions, the antioxidative capacity of the glycinate and glycinate-methylester derivatives slightly exceeded that of the respective parent compounds. Summarizing the results it can be concluded that with respect to possible interactions with the CYP system in vivo and thus with the biotransformation of other concomitantly administered compounds no advantages of the glycinate or glycinate methylester derivatives over their parent fibrates are to be expected. Only the antioxidative capacity of the derivatives was somewhat higher than that of the parent substances, though most probably only of minor therapeutical relevance.
Lupp
Amelie
A
Institute of Pharmacology and Toxicology, Friedrich Schiller University Jena, Jena, Germany. alup@mti-n.uni-jena.de
Karge
Elke
E
Hopf
Heiner
H
Machts
Heike
H
Oelschläger
Herbert
H
Fleck
Christian
C
D000818:Animals; D021461:Animals, Outbred Strains; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004951:Esterification; D005998:Glycine / Q000031:analogs & derivatives / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000737:chemistry / Q000378:metabolism*; D007527:Isoenzymes; D015227:Lipid Peroxidation; D008163:Luminescent Measurements; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
D000960:Hypolipidemic Agents; D007527:Isoenzymes; D003577:Cytochrome P-450 Enzyme System; D006861:Hydrogen Peroxide; D005998:Glycine