Comparative Expression of Liver Cytochrome P450-dependent Monooxygenases in the Horse and in other Agricultural and Laboratory Species

Nebbia, Carlo; Dacasto, Mauro; Giaccherino, A. Rossetto; Albo, A. Giuliano; Carletti, Monica

doi:10.1016/s1090-0233(02)00174-0

Cited by 118 publications

(145 citation statements)

References 40 publications

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“…The O-dealkylation ranged from 20 -120 pmol/ mg/min in minipigs and the activities for the different conventional strains were 40 and 100 pmol/mg prot./min at a substrate concentration of 5 µM [5,9]. In one study the Vmax for EROD activity was found for both humans and micropigs.…”

Section: Cyp1amentioning

confidence: 98%

“…The minipigs contained the highest activity of total P450 (0.81 nmol/prot) and the different strains of conventional pigs contained 0.57 nmol/mg prot. [9], 0,22 nmol/mg prot [8], and 0.46 nmol/mg, respectively [5]. This shows that the conventional pigs have a P450 activity comparable to the total human P450 of 0.43nmol/mg protein and 0.26 nmol/mg protein in Caucasian and Japanese, respectively [10], whereas the minipigs total P450 is about 2 -3 fold higher.…”

Section: Total P450mentioning

confidence: 99%

“…Human CYP1A activity is also present in porcine liver microsomes i.e. ethoxy-and methoxyresorufin O-dealkylation (EROD and MROD) [9]. The O-dealkylation of 7-ethoxyresorufin was found to be sex related in minipigs but not in conventional pigs [5].…”

Section: Cyp1amentioning

confidence: 99%

“…Several of these subfamilies i.e. CYP1A, CYP2A, CYP2B, CYP2C, CYP2E and CYP3A have been characterized for the pig and minipig (micropig) during the past few years using primary hepatocyte cultures or hepatocyte microsomes [1,2,3,4,5,6,7,8,9]. The characterization is done in order to enable the evaluation of the pig as a test animal for human drug metabolism.…”

Section: Introductionmentioning

confidence: 99%

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Porcine Cytochrome P450 and Metabolism

Skaanild¹

2006

CPD

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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.

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Section: Cyp1amentioning

confidence: 98%

Section: Total P450mentioning

confidence: 99%

Section: Cyp1amentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Porcine Cytochrome P450 and Metabolism

Skaanild¹

2006

CPD

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“…With few exceptions, the ability in forming such complexes in vitro exhibited by many amino drugs including tiamulin and certain macrolides may be substantially related to their inhibitory potency towards the P450-mediated biotransformation of compounds being substrates of the complexed P450s themselves [16,22,23,24]. In this respect, it should be noted that liver CYP 3A is one of the most versatile mammalian CYP isoforms being able to metabolise a large number of drugs and xenobiotics [12] and that it appears to be constitutively well expressed in rabbits [8,15]. Taking into account that factors such as the route of exposure, the dosage and the concentration reached in liver may affect MI complex formation in living animals, our findings indicate that the potential for relevant drug-drug interactions (even at the residue level) might be expected in the rabbit mainly for tiamulin and erythromycin, and to a lesser extent for TAO, roxithromycin and tylosin, while the risk for tilmicosin and spiramycin should be reasonably very low.…”

Section: Discussionmentioning

confidence: 99%

In vitro formation of metabolic-intermediate cytochrome P450 complexes in rabbit liver microsomes by tiamulin and various macrolides

Carletti

Gusson²,

Zaghini³

et al. 2003

Vet. Res.

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-Tiamulin and a number of macrolides were evaluated as to their ability in forming metabolic-intermediate (MI) complexes with cytochrome P450 in liver microsomes from rabbits bred for meat production. Complex formation, which occurred only in preparations where the expression of P450 3A was increased as the result of rifampicin pre-treatment and with different kinetics, was in the order tiamulin > erythromycin > TAO » roxithromycin » tylosin and did not take place with tilmicosin and spiramycin. Most of the tested compounds underwent an oxidative N-dealkylation and a good relationship could be found between the rate of N-dealkylase activity in induced preparations and the aptitude in generating MI complexes. Although the results from in vitro studies should be interpreted with caution, it is suggested that the potential for in vivo drug interactions also exists in the rabbit for tiamulin and for four out of the six tested macrolides. tiamulin / macrolide / rabbit / metabolic-intermediate complex / in vitro

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Pharmacokinetics and Toxicokinetics in Drug Safety Evaluation

Gad

2002

Drug Safety Evaluation

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Comparative Expression of Liver Cytochrome P450-dependent Monooxygenases in the Horse and in other Agricultural and Laboratory Species

Cited by 118 publications

References 40 publications

Porcine Cytochrome P450 and Metabolism

Porcine Cytochrome P450 and Metabolism

In vitro formation of metabolic-intermediate cytochrome P450 complexes in rabbit liver microsomes by tiamulin and various macrolides

Pharmacokinetics and Toxicokinetics in Drug Safety Evaluation

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