Differential expression ofCYP3A12andCYP3A26mRNAs in canine liver and intestine

Mealey, Katrina L.; Jabbes, Mohamed; Spencer, Erick S.; Akey, Joshua M.

doi:10.1080/00498250802446146

Cited by 25 publications

(16 citation statements)

References 14 publications

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“…Human CYP3A4 and CYP3A5 subfamilies represent ϳ30% of total liver P450s and contribute to the metabolism of 45 to 60% of the currently used drugs (Testa and Krämer, 2008b). In dog liver, the level for CYP3A12 mRNA was markedly lower than the level for CYP3A26, which is in agreement with previous results reported by Mealey et al (2008). However, it is uncertain to what extent the higher CYP3A26 expression translates into a larger impact of CYP3A26 on drug metabolism, because CYP3A26 shows generally lower hydroxylase activity than CYP3A12 (Fraser et al, 1997).…”

Section: Gapdh-normalized Mrna Levels In the Liversupporting

confidence: 89%

“…The beagle dog is a commonly used model to assess oral bioavailability, evaluate new formulations, investigate the influence of food on the absorption of new drug compounds (Mealey et al, 2008), and as the standard species for preclinical safety evaluations (Keenan and Vidal, 2006). Although the gastric pH, motility, and emptying time in fasted dog and human stomach are reported to be comparable, a slower gastric emptying and a lower pH were observed postprandially in dogs compared with humans (Dressman, 1986).…”

Section: Introductionmentioning

confidence: 99%

“…The reported studies in dogs mainly focus on the expression and catalytic activity of metabolic enzymes in the liver (Kyokawa et al, 2001;Mills et al, 2010). Less is known about the intestinal expression distribution of cytochromes P450 (P450s), UDP-glucuronosyltransferases (UGTs) (Bock et al, 2002;Mealey et al, 2008), and transporters (Conrad et al, 2001) or about P450 substrate specificity (Fraser et al, 1997;Turpeinen et al, 2007;Locuson et al, 2009) and intersubject variability in expression.…”

Section: Introductionmentioning

confidence: 99%

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Expression Profiles of Metabolic Enzymes and Drug Transporters in the Liver and along the Intestine of Beagle Dogs

Haller¹,

Schuler²,

Lazic³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Beagle dogs are widely used in preclinical pharmacokinetic, safety, and formulation studies. However, little is known about intestinal and hepatic distribution of major enzymes and transporters involved in oral absorption and presystemic drug metabolism. We characterized mRNA levels of CYP3A12, CYP3A26, CYP2D15, UGT1A6, ABCB1 (MDR1), ABCC1 (MRP1), ABCG2 (BCRP), SLC15A1 (PEPT1), and SLC22A1 (OCT1) in dog liver and along the intestine by real-time quantitative reverse transcription-polymerase chain reaction. Tissue protein levels of CYP2D15, MDR1, and PEPT1 were obtained by Western blot. Gene distribution and expression variability was statistically described by a generalized additive mixed model smoothing function and correspondence analysis. Results were compared with the expression pattern known for the human orthologs. Hepatic mRNA levels for metabolic enzymes were generally higher than those for membrane transporters, whereas in the intestine the opposite was observed. Hepatic mRNA levels followed the order CYP2D15 > UGT1A6 Ϸ CYP3A26 > ABCB1 Ϸ SLC15A1 Ϸ SLC22A1 > ABCG2 > ABCC1 Ϸ CYP3A12. Along the gut, the genes were differentially distributed with greatest expression in duodenum/upper jejunum (ABCG2), middle jejunum (ABCB1 and SLC15A1), or in cecum/colon (ABCC1 and CYP2D15). CYP3A12, CYP3A26, SLC22A1, and UGT1A6 had a rather uniform expression. Intestinal mRNA profiles of CYP2D15, ABCB1, and SLC15A1 correlated with the respective protein levels. Canine CYP3A12/26, CYP2D15, and ABCB1 colonic distributions differed from those of human orthologs, whereas UGT1A6, ABCC1, ABCG2, SLC15A1, and SLC22A1 were comparable to those of humans in both small and large intestine. We aim to apply these data to better interpret pharmacokinetic studies in dogs with respect to their human relevance.

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Section: Gapdh-normalized Mrna Levels In the Liversupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Expression Profiles of Metabolic Enzymes and Drug Transporters in the Liver and along the Intestine of Beagle Dogs

Haller¹,

Schuler²,

Lazic³

et al. 2012

Drug Metab Dispos

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show abstract

“…In rat, CYP3A1 and CYP3A18 are major CYP3A genes in liver, while three genes of CYP3A including CYP3A62, CYP3A18 and CYP3A9 are abundantly expressed in rat small intestine [5]. Overall, intestinal CYP3A expression is much lower than the hepatic expression in dog and rat, compared to humans [5,6,9,12]. Thus, the pattern of tissue distribution of feline CYP3A131 was similar to human CYP3A4.…”

Section: Novel Cyp3a Isoforms In Catsmentioning

confidence: 94%

“…CYP3A4 is predominant and occupies about 30% of CYP proteins in liver [12] and about 80% in small intestine of humans [9]. CYP3A26 is the dominant CYP3A gene in dog liver, while CYP3A12 expression is greater than CYP3A26 in small intestine [6]. In rat, CYP3A1 and CYP3A18 are major CYP3A genes in liver, while three genes of CYP3A including CYP3A62, CYP3A18 and CYP3A9 are abundantly expressed in rat small intestine [5].…”

Section: Novel Cyp3a Isoforms In Catsmentioning

confidence: 99%

Expression of Two Novel Cytochrome P450 3A131 and 3A132 in Liver and Small Intestine of Domestic Cats

et al. 2011

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ABSTRACT. Cytochrome P450 3A (CYP3A) is the major subfamily of CYP, one of the most important metabolizing enzymes for drugs in humans and other mammals. We found two novel CYP3A genes, CYP3A131 and CYP3A132 in domestic cats (Felis catus). Both feline CYP3A proteins consist of 504 deduced amino acids and show high identity with canine CYP3A homologues and those of some artiodactyls. CYP3A131 transcripts were expressed predominantly in liver and small intestine, and to a negligible extent in other tissues, including brain, heart, kidney and lung. CYP3A132 expression was only detected in liver with much lesser amount. These results suggest the possible major role of CYP3A131 in xenobiotic metabolism including first-pass effects in domestic cats.

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CYP450 Enzymes in Drug Discovery and Development: An Overview

Das

Prakash

2012

Encyclopedia of Drug Metabolism and Interactions

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Cytochrome P450 enzymes play an important role in the metabolism of foreign molecules (drugs and environmental chemicals) and endogenous compounds. This large enzyme family facilitates to eliminate xenobiotics from the body and catalyzes the catabolism of endogenous compounds for their physiological functions. In this chapter, we describe the most recent advances in our knowledge and application of P450 enzymes in drug discovery and development with particular emphasis on their involvement in the metabolism of drugs. In addition, we have also summarized the basic catalytic activity of this enzyme family, commonly observed biotransformation in drugs, the species and ethnic variation in the expression of P450 enzymes, and the tools used to extrapolate metabolism and toxicity in animals to humans.

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Differential expression ofCYP3A12andCYP3A26mRNAs in canine liver and intestine

Cited by 25 publications

References 14 publications

Expression Profiles of Metabolic Enzymes and Drug Transporters in the Liver and along the Intestine of Beagle Dogs

Expression Profiles of Metabolic Enzymes and Drug Transporters in the Liver and along the Intestine of Beagle Dogs

Expression of Two Novel Cytochrome P450 3A131 and 3A132 in Liver and Small Intestine of Domestic Cats

CYP450 Enzymes in Drug Discovery and Development: An Overview

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