Determining the best animal model for human cytochrome P450 activities: a comparison of mouse, rat, rabbit, dog, micropig, monkey and man.
1. In the present study, nine cytochrome P450 enzyme activities in seven species were characterized to allow a practical means of comparing this important metabolic step between various test animals and man. 2. Enzyme activities and kinetic parameters were first determined towards marker substrates for human cytochrome P450 enzymes. Inhibition profiles were then determined with both antibodies directed against various cytochrome P450 enzymes and with chemical inhibitors. 3. Both the enzyme kinetic parameters/enzyme activities, and the inhibition profiles obtained for the animal species were compared with those obtained for human liver microsomes in order to postulate the animal species most similar to man with regard to each individual cytochrome P450 enzyme activity. 4. It was found that, as expected, none of the tested species was similar to man for all the measured P450 enzyme activities, but that in each species only some of the P450 enzyme activities could be considered as similar to man. 5. When it is known which human cytochrome P450 enzymes are involved in the metabolism of a compound, the comparative data presented here can be used for selecting the most suitable species for in vitro and in it no experiments.
Bogaards
J J
JJ
Department of Kinetics and Metabolism, AJ Zeist, The Netherlands. Bogaards@voeding.tno.nl
Bertrand
M
M
Jackson
P
P
Oudshoorn
M J
MJ
Weaver
R J
RJ
van Bladeren
P J
PJ
Walther
B
B
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases; D001571:Benzoflavones / Q000494:pharmacology; D019363:Cytochrome P-450 CYP1A1 / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D065637:Cytochrome P-450 CYP2A6; D065702:Cytochrome P-450 CYP2B6; D019389:Cytochrome P-450 CYP2D6; D019392:Cytochrome P-450 CYP2E1; D042926:Cytochrome P-450 CYP4A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology / Q000378:metabolism*; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000187:drug effects / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000378:metabolism*; D006899:Mixed Function Oxygenases; D010089:Oxidoreductases, N-Demethylating; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases
D000911:Antibodies, Monoclonal; D001571:Benzoflavones; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; C011512:alpha-naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D019363:Cytochrome P-450 CYP1A1; D065637:Cytochrome P-450 CYP2A6; D065702:Cytochrome P-450 CYP2B6; D019389:Cytochrome P-450 CYP2D6; D039181:Steroid 16-alpha-Hydroxylase; D042926:Cytochrome P-450 CYP4A; D010089:Oxidoreductases, N-Demethylating