Porcine cytochrome P450 and metabolism.
The pig and especially the minipig are becoming increasingly used as a test animal both in pharmacological and toxicological testing of new compounds. The minipig is used because of its size, it is easy to handle and less test substrate is required. When using an animal species for testing it is of importance to know if the test animal's posses the same abilities to metabolize drugs as humans. Some of the P450 enzymes have been characterized in the pig regarding substrate specificity, inhibition and regulation. The porcine enzymes CYP1A, CYP2A and CYP3A all metabolize the same test substrates as the human enzymes, whereas the enzymes CYP2B, CYP2D, and CYP2E in pig on the other hand seem to be different from the human enzymes concerning metabolism of the well know test substrates. Some of the porcine enzymes have been sequenced i.e. CYP1A, CYP2A, CYP2B, CYP2D, CYP2E and CYP3A and not surprisingly the porcine CYPs that metabolize the human test substrates are about 75% identical in cDNA sequences. What is needed is inhibitory antibodies against each of the porcine enzymes, in order to test whether a test compound is metabolized by one or the other enzyme. Until now chemical inhibitors have been used, but they are rarely 100% specific. Anti-human inhibitory antibodies have also been used, but they may not recognize the porcine enzyme and therefore will not inhibit the reaction. Antibodies for immunoblotting would also make it possible to estimate how much of the total P450 the individual enzymes comprise. From what is known about the porcine P450, it can be concluded that the pig seems to be a good test species if CYP1A, CYP2A or CYP3A are involved in the metabolism of the test compound, depending on the contribution of other enzymes in competing pathways.
Skaanild
Mette Tingleff
MT
The Royal Veterinary and Agricultural University, Department of Veterinary Pathobiology, Ridebanevej 9, DK-1870 Frederiksberg, Denmark. mts@kvl.dk
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000502:physiology; D065702:Cytochrome P-450 CYP2B6; D019389:Cytochrome P-450 CYP2D6 / Q000502:physiology; D019392:Cytochrome P-450 CYP2E1 / Q000502:physiology; D051544:Cytochrome P-450 CYP3A / Q000502:physiology; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D010089:Oxidoreductases, N-Demethylating / Q000502:physiology; D013250:Steroid Hydroxylases / Q000502:physiology; D013552:Swine / Q000378:metabolism*
C400322:cytochrome P-450 CYP2C subfamily; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C029009:steroid hormone 7-alpha-hydroxylase; D010089:Oxidoreductases, N-Demethylating