Comparison of mouse and rat cytochrome P450-mediated metabolism in liver and intestine.
The liver is considered to be the major site of first-pass metabolism, but the small intestine is also able to contribute significantly. The improvement of existing in vitro techniques and the development of new ones, such as intestinal slices, allow a better understanding of the intestine as a metabolic organ. In this paper, the formation of metabolites of several human CYP3A substrates by liver and intestinal slices from rat and mouse was compared. The results show that liver slices exhibited a higher metabolic rate for the majority of the studied substrates, but some metabolites were produced at a higher rate by intestinal slices, compared with liver slices. Coincubation with ketoconazole inhibited the metabolic conversion in intestinal slices almost completely, but inhibition was variable in liver slices. To better understand the role of CYP3A in mice, we studied the relative mRNA expression of different CYP3A isoforms in intestine and liver from mice because, in this species, CYP3A expression has not been well described in these organs. It was found that in mice, CYP3A13 is more expressed in the intestine, whereas CYP3A11, CYP3A25, and CYP3A41 are more expressed in the liver, comparable to similar findings in the rat. Altogether, these data demonstrate that, in addition to liver, the intestine from mouse and rat may have an important role in the process of first-pass metabolism, depending on the substrate. Moreover, we show that intestinal slices are a useful in vitro technique to study gut metabolism.
Preclinical Development, Nerviano Medical Sciences, Viale Pasteur 10, 20014 Nerviano (MI), Italy. marcella.martignoni@nervianoms.com
Marcella
M
Martignoni
Geny
G
Groothuis
Ruben
R
de Kanter
D000818:Animals; D002220:Carbamazepine / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006915:Hydroxytestosterones / Q000378:metabolism; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects / Q000201:enzymology; D007654:Ketoconazole / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008861:Microsomes / Q000378:metabolism; D008874:Midazolam / Q000378:metabolism; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity
D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D006915:Hydroxytestosterones; D008565:Membrane Proteins; D012333:RNA, Messenger; D002220:Carbamazepine; D003577:Cytochrome P-450 Enzyme System; C408695:Cyp3a41a protein, mouse; D010088:Oxidoreductases; C496508:Cyp3a11 protein, mouse; C496509:Cyp3a13 protein, mouse; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam; D007654:Ketoconazole