Evidence for the catalysis of Dextromethorphan O-demethylation by a CYP2D6-like enzyme in pig liver

Jurima-Romet, Malle; Casley, William L.; Leblanc, Catherine; Nowakowska, Margeryta

doi:10.1016/s0887-2333(00)00016-3

Cited by 21 publications

(24 citation statements)

References 26 publications

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“…Low debrisoquine 4-hydroxylase activity of domestic pig CYP2D25 was confirmed by an assay using recombinant enzymes (Hosseinpour and Wikvall, 2000). By contrast, Jurima-Romet et al (2000) demonstrated the evidence for the catalysis of dextromethorphan O-demethylation by a CYP2D6-like enzyme in domestic pig liver. These discrepancies raised the question of whether CYP2D enzymes of domestic or miniature pigs retain the functional similarity to human CYP2D6.…”

Section: Resultsmentioning

confidence: 86%

Cloning Cyp2d21 and Cyp3a22 Cdnas From Liver of Miniature Pigs

Sakuma

Shimojima²,

Miwa³

et al. 2004

Drug Metab Dispos

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ABSTRACT:To compare the identity of the primary structure of drug-metabolizing cytochrome P450 between miniature pigs and humans, two cDNA clones, coding for miniature pig CYP2D21 and CYP3A22, were isolated. The deduced amino acid sequences of CYP2D21 and CYP3A22 were 78.3 and 75.0% identical to human CYP2D6 and CYP3A4, respectively. These values were nearly the same as those of bovine, dog, and some rodent isoforms, and 12.2 to 18.4% lower than those of nonhuman primates such as cynomolgus monkeys, Japanese monkey, and marmosets. These data indicate that miniature pig P450s are genetically not so close as monkey P450s to human P450s as previously expected. The recombinant CYP2D21 enzyme, however, showed bufuralol 1-hydroxylase activity, suggesting that miniature pig CYP2D21 is capable of metabolizing some of the same substrates associated with human CYP2D6 despite its low identity to human counterparts.

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Section: Resultsmentioning

confidence: 86%

Cloning Cyp2d21 and Cyp3a22 Cdnas From Liver of Miniature Pigs

Sakuma

Shimojima²,

Miwa³

et al. 2004

Drug Metab Dispos

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“…Microsomes isolated from the liver of pigs dealkylated methoxy-and ethoxyresorufin implying the expression of CYP1 [12,20,47,51,52]. In support of this inference, antibodies to rat CYP1A recognised a single immunoreacting band in hepatic microsomes [44,53], but no immunoreactivity was detected by other researchers using similar antibody preparations [52,54]. Use of rabbit anti-CYP1A antibodies revealed a single cross-reacting protein, but a second immunoreacting protein was evident closely below, presumably CYP1A1, when the animals were treated with β-naphthoflavone [52].…”

Section: Cyp1 Familymentioning

confidence: 85%

“…Use of rabbit anti-CYP1A antibodies revealed a single cross-reacting protein, but a second immunoreacting protein was evident closely below, presumably CYP1A1, when the animals were treated with β-naphthoflavone [52]. Immunoblotting with human CYP1A2 antibodies revealed a single band with an apparent molecular mass corresponding to the human protein [54], but no immunoreacting band could be detected in more recent studies utilising similar antibody preparations [47]. Finally, pig hepatic preparations could metabolically convert heterocyclic amines, such as 2-amino-3-methylimidazo-[4, 5-f]quinoline (IQ), to mutagenic intermediates in the Ames test, a pathway which is selectively catalysed by CYP1A2 in rodents and humans ( Table 2) [55].…”

Section: Cyp1 Familymentioning

confidence: 97%

Cytochrome P450 Expression in the Liver of Food-Producing Animals

Ioannides

2006

CDM

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A number of enzyme systems participate in the metabolism of chemicals, but undoubtedly the most important are the cytochromes P450 (CYP). It is a versatile enzyme system, capable of metabolising structurally diverse chemicals. To achieve this broad substrate specificity it exists as a superfamily of enzymes, each family being characterised by different substrate specificity; families CYP1, CYP2 and CYP3 are responsible for the metabolism of exogenous chemicals. Although our current knowledge of the expression and function of cytochromes P450 in humans and laboratory animals is extensive, little is known about this enzyme system in food-producing animals, despite its dominant role in the metabolism of veterinary drugs, and the crucial role it plays in controlling the levels of drug and other chemical residues in edible tissues and food products that humans consume, a matter of major current concern. Most studies dealing with the expression of cytochromes P450 in food-producing animals utilised substrate probes defined in rats and humans and/or antibodies raised to rat or human antigens. Such an approach can prove misleading as it assumes that orthologue proteins in other animals share the same substrate specificity and, moreover, although antibodies raised to human or rat antigens may recognise epitopes in other species, they do not constitute unequivocal proof that the detected proteins are structurally identical. Despite these drawbacks, there is substantial experimental evidence that CYP1, CYP2 and CYP3 families are expressed in food-producing animals, but their role in the metabolism of veterinary drugs and other xenobiotics has not been addressed.

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“…The cross-reactivity of human CYP3A4 antibodies with pig liver microsomal protein suggests at least partial homology between the human CYP3A4 and its equivalent isoform in pig liver. Furthermore, human cDNA probe for CYP3A4 hybridized to pig liver mRNA indicated that the pig CYP3A29 gene has considerable homology to the human gene (Jurima-Romet et al, 2000). Minipigs also contained proteins similar to human CYP3A4 and/or 3A5 as shown by immunoblotting (Anzenbacher et al, 1998).…”

Section: Variability In the Formation Of Paclitaxel Metabolitesmentioning

confidence: 99%

“…Minipigs and pigs might be suitable experimental animals to predict metabolic pathways in humans, because the most important human P450 isoform (CYP3A) has ortholog isoform present in minipigs at comparable levels and activities, and there is no need to induce P450 enzyme levels (Anzenbacher et al, 1998). Moreover, CYP3A29 has been identified in the pig according to European Molecular Biology Laboratory/GenBank/DNA Data Bank of Japan databank submissions (Jurima-Romet et al, 2000) as an ortholog of human CYP3A4. Furthermore, metabolism in pigs supposedly closely resembles that of humans, and pig livers have even been considered future candidates for human transplantation.…”

mentioning

confidence: 99%

Different in Vitro Metabolism of Paclitaxel and Docetaxel in Humans, Rats, Pigs, and Minipigs

Václavíková

Souček²,

Svobodová³

et al. 2004

Drug Metab Dispos

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ABSTRACT:We investigated cytochrome P450 (P450)-catalyzed metabolism of the important cancer drugs paclitaxel and docetaxel in rat, pig, minipig, and human liver microsomes and cDNA-expressed P450 enzymes. In rat microsomes, paclitaxel was metabolized mainly to C3-hydroxypaclitaxel (C3-OHP) and to a lesser extent to C2-hydroxypaclitaxel (C2-OHP), di-hydroxypaclitaxel (di-OHP), and another unknown monohydroxylated paclitaxel. In pig and minipig microsomes, this unknown hydroxypaclitaxel was the main metabolite, whereas C3-OHP was a minor product. In minipigs, C2-OHP was the next minor product. In human liver microsomes, 6␣-hydroxypaclitaxel (6␣-OHP) was the main metabolite, followed by C3-OHP and C2-OHP. Among different cDNAexpressed human P450 enzymes (CYP1A2, 1B1, 2A6, 2C9, 2E1, and 3A4), only CYP3A4 enzyme formed C3-OHP and C2-OHP. Docetaxel was metabolized in pig, minipig, rat, and human liver microsomes mainly to hydroxydocetaxel (OHDTX), whereas CYP3A-induced rat microsomes produced primarily diastereomeric hydroxyoxazolidinones. Human liver microsomes from 10 different individuals formed OHDTX at different rates correlated with CYP3A4 content. Troleandomycin as a selective inhibitor of CYP3A inhibited the formation of C3-OHP, C2-OHP, and di-OHP, as well as the unknown OHP produced in rat, minipig, and pig microsomes. In human liver microsomes, troleandomycin inhibited C3-OHP and C2-OHP formation, and a suitable inhibitor of human CYP2C8, fisetin, strongly inhibited the formation of 6␣-OHP, known to be catalyzed by human CYP2C8. In conclusion, the metabolism of docetaxel is the same in all four species, but metabolism of paclitaxel is different, and 6␣-OHP remains a uniquely human metabolite. Pigs and minipigs compared with each other formed the same metabolites of paclitaxel.

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Evidence for the catalysis of Dextromethorphan O-demethylation by a CYP2D6-like enzyme in pig liver

Cited by 21 publications

References 26 publications

Cloning Cyp2d21 and Cyp3a22 Cdnas From Liver of Miniature Pigs

Cloning Cyp2d21 and Cyp3a22 Cdnas From Liver of Miniature Pigs

Cytochrome P450 Expression in the Liver of Food-Producing Animals

Different in Vitro Metabolism of Paclitaxel and Docetaxel in Humans, Rats, Pigs, and Minipigs

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