Porcine Cytochrome P450 and Metabolism

Abstract

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.

Plasma oxylipin profiling identifies polyunsaturated vicinal diols as responsive to arachidonic acid and docosahexaenoic acid intake in growing piglets

“…Based on the high homology between the pig and human genome, high sequence homology between human and porcine COX and LOX enzymes can be expected. Some porcine CYP enzymes showed about 70-83% homology to human forms and metabolized the same test substrates ( 37 ). This is the fi rst study to report on the dose responsiveness of fatty acid-derived oxylipins to dietary intake of ARA and DHA during early postnatal development in piglets.…”

“…We considered the pig model to be a relatively representative model of the human because the LCPUFA metabolism and enzymes are highly comparable ( 36,37,65 ). Our data revealed no signifi cant change in circulating COX or LOX products with increasing ARA or DHA in the diet.…”

Modulation of porcine cytochrome P450 enzyme activities by surgical castration and immunocastration

“…p-Nitrophenol hydroxylation is often used as a marker of CYP2E1 (Koop et al, 1989;Sohn et al, 2001). In pigs, however, the selectivity of this substrate is somewhat questionable, given that in porcine liver microsomes, p-nitrophenol is partially metabolized by CYP2A (Skaanild, 2006).…”

“…p-Nitrophenol hydroxylation is often used as a marker of CYP2E1 (Koop et al, 1989;Sohn et al, 2001). In pigs, however, the selectivity of this substrate is somewhat questionable, given that in porcine liver microsomes, p-nitrophenol is partially metabolized by CYP2A (Skaanild, 2006).The role of gender in the activities of some CYP450 enzymes is well established in many species, e.g., humans (Parkinson et al, 2004;Scandlyn et al, 2008), rats (Mugford and Kedderis, 1998), minipigs and conventional pigs (Skaanild and Friis, 1999;Zamaratskaia et al, 2006). Castration of Meishan male pigs resulted in increased mRNA, protein levels and activities of CYP1A enzymes (Kojima et al, 2008).…”

Pigs in Toxicology

“…Porcine CYP2A19 is 99% homologous between Göttingen and conventional breed pigs. Female Göttingens have 70Â higher activity than males, but when males are castrated, the activity of CYP2A in these animals increases 10Â (Gillberg, Skaanild, and Friis 2006;Skaanild 2006). Sex differences have also been reported in Yucatans, where the females have 5Â higher activity than males (Bogaards et al 2000).…”