Identification of the novel canine CYP1A2 1117 C&gt;T SNP causing protein deletion

Tenmizu, Daisuke; Endo, Yasuhisa; Noguchi, Kaoru; Kamimura, Hidetaka

doi:10.1080/00498250412331285436

Cited by 41 publications

(37 citation statements)

References 22 publications

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“…A list of identified breed-specific idiosyncrasies that can influence drug absorption and metabolism are provided in Tables III and IV ( [40][41][42][43][44][45][46][47][48][49][50][51][52][53][54]. Table III includes recognized metabolic idiosyncrasies and Table IV includes physiologic idiosyncrasies.…”

Section: Breed-related Differences In Pharmacokinetics and Pharmacodymentioning

confidence: 99%

Pharmacogenetic and Metabolic Differences Between Dog Breeds: Their Impact on Canine Medicine and the Use of the Dog as a Preclinical Animal Model

Fleischer

Sharkey

Mealey

et al. 2008

AAPS J

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Abstract. There is limited information describing species related pharmacogenetic differences in animals. Despite the lack of genetic information in veterinary medicine, breed specific responses to endogenous and exogenous substances have been reported across many species. This finding underscores the importance of obtaining insight into the genotypic and phenotypic variation present across breeds. This article provides a summary of the literature pertaining to canine breed differences in physiology, drug response, drug pharmacokinetics, and metabolic idiosyncrasies. The existing knowledge of pedigrees and the known phenotypes and genotypes of dogs provides important information for determining mode of inheritance, penetration, and other major characteristics of heritable traits. Understanding these breed differences will improve canine population predictions (for canine drug products) and may be of value when extrapolating toxicology data from dogs to humans.

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Section: Breed-related Differences In Pharmacokinetics and Pharmacodymentioning

confidence: 99%

Pharmacogenetic and Metabolic Differences Between Dog Breeds: Their Impact on Canine Medicine and the Use of the Dog as a Preclinical Animal Model

Fleischer

Sharkey

Mealey

et al. 2008

AAPS J

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“…The canine liver microsomes were prepared and the CYP1A2 1117 CϾT SNP genotyping method was performed as described by Tenmizu et al (2004a). YM-64227 (5 M) was incubated in a reaction mixture (0.5 ml) consisting of 0.1 mg/ml liver microsomes, a NADPH-generating system (1.3 mM NADP, 3.3 mM glucose 6-phosphate, 0.4 U/ml glucose-6-phosphate dehydrogenase, and 3.3 mM MgCl 2 ), 0.1 mM EDTA, and 100 mM Na/K-phosphate buffer (pH 7.4).…”

Section: Methodsmentioning

confidence: 99%

“…In previous studies, a novel CYP1A2 1117 CϾT single nucleotide polymorphism (SNP) was found in beagle dogs, which are used extensively in pharmacology and safety assessment studies (Tenmizu et al, 2004a;Mise et al, 2004a). This SNP resulted in an amino acid change from an Arg codon to a stop codon at position 373, yielding an inactive enzyme.…”

Section: -mentioning

confidence: 99%

“…In addition, it maintains the ability to inhibit antigen-induced airway responses. For this reason, YM-64227 promises to be a highly effective and safe drug when used as an antiasthmatic or antiinflammatory drug (Iwata et al, 1998).In previous studies, a novel CYP1A2 1117 CϾT single nucleotide polymorphism (SNP) was found in beagle dogs, which are used extensively in pharmacology and safety assessment studies (Tenmizu et al, 2004a;Mise et al, 2004a). This SNP resulted in an amino acid change from an Arg codon to a stop codon at position 373, yielding an inactive enzyme.…”

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confidence: 99%

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Elucidation of the Effects of the CYP1A2 Deficiency Polymorphism in the Metabolism of 4-Cyclohexyl-1-ethyl-7-methylpyrido[2,3-d]pyrimidine-2-(1H)-one (YM-64227), a Phosphodiesterase Type 4 Inhibitor, and Its Metabolites in Dogs

Tenmizu

Noguchi²,

Kamimura³

2006

Drug Metab Dispos

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ABSTRACT:The canine CYP1A2 1117 C>T single nucleotide polymorphism is responsible for a substantial portion of the interindividual variability seen in the pharmacokinetics of 4-cyclohexyl-1-ethyl-7-methylpyrido[2,3-d]pyrimidine-2-(1H)-one (YM-64227). The purpose of this study is to investigate the contribution of CYP1A2 to the metabolism of YM-64227 and its five metabolites (MM-1 to MM-5), as well as to determine the interindividual variability between the pharmacokinetic profiles of the compounds with respect to the CYP1A2 deficiency polymorphism. ␣-Naphthoflavone and anti-CYP1A1/2 antibody inhibited the metabolic activities at which MM-2 and MM-3 were formed from YM-64227 in C/C-and C/T-type microsomes. In T/T type, the rate of MM-2 and MM-3 formation was lower, and ␣-naphthoflavone and anti-CYP1A1/2 antibody were shown to have no effect. A positive correlation between the overall metabolism of YM-64227 and phenacetin O-deethylation, a CYP1A2 activity marker, was observed in all the genotypes. The in vitro metabolic clearances in the T/T type of MM-1, MM-3, MM-4, and MM-5 were less than 50% lower than those in the C/C type. The anti-CYP1A1/2 antibody inhibited the metabolism of MM-1, MM-3, MM-4, and MM-5 in the C/C and C/T types. These results suggest that the formation of MM-2 and MM-3 from YM-64227 is catalyzed by CYP1A2, and that CYP1A2 contributes mainly to the subsequent metabolism of the primary metabolites of YM-64227, with the exception of MM-2. It is possible that the interindividual variability of YM-64227 with respect to the CYP1A2 deficiency polymorphism is caused by a decrease in the metabolic activities of both the unchanged drug and its metabolites. 4-) is a novel phosphodiesterase type 4 inhibitor. Unlike other phosphodiesterase type 4 inhibitors, YM-64227 does not induce the emetic effects that normally accompany the anti-inflammatory activity. In addition, it maintains the ability to inhibit antigen-induced airway responses. For this reason, YM-64227 promises to be a highly effective and safe drug when used as an antiasthmatic or antiinflammatory drug (Iwata et al., 1998).In previous studies, a novel CYP1A2 1117 CϾT single nucleotide polymorphism (SNP) was found in beagle dogs, which are used extensively in pharmacology and safety assessment studies (Tenmizu et al., 2004a;Mise et al., 2004a). This SNP resulted in an amino acid change from an Arg codon to a stop codon at position 373, yielding an inactive enzyme. The T-allele frequency was 0.39, which suggests that 10 to 15% of the dogs would not express the CYP1A2 protein. This CYP1A2 deficiency polymorphism causes significant changes in the pharmacokinetic profile of YM-64227 in beagle dogs (Tenmizu et al., 2006). The plasma concentrations of the unchanged drug and five of its metabolites (MM-1 to MM-5, Fig. 1) were determined after both intravenous and oral administration of YM-64227 to genotyped dogs (C/C, C/T, and T/T groups). After a single oral administration, the maximum plasma concentration and absolute bioavailability of YM-64227 in ...

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“…In humans, CYP1A2 polymorphisms in the coding region are rare and only occasionally appear to decrease enzyme activity (Faber et al, 2005). A CYP1A2 polymorphism in beagle dogs has been reported (Tenmizu et al, 2004). The mutation is a single nucleotide polymorphism, CYP1A2 1117 CϾT, which results in an amino acid change from arginine to an early stop codon at position 373 (truncated inactive protein).…”

Section: Introductionmentioning

confidence: 99%

Phenacetin Pharmacokinetics in CYP1A2-Deficient Beagle Dogs

Whiterock

Morgan²,

Lentz³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Phenacetin is widely used as an in vitro probe to measure CYP1A2 activity across species. To investigate whether phenacetin can be used as an in vivo probe substrate to phenotype CYP1A2 activity in dogs, beagle dogs previously genotyped for a single nucleotide polymorphism that yields an inactive CYP1A2 protein were selected and placed into one of three groups: CC (wild-type), CT (heterozygous), or TT (homozygous mutants). The dogs were dosed with phenacetin orally at 5 and 15 mg/kg and intravenously at 15 mg/kg. Plasma samples were analyzed by liquid chromatography-tandem mass spectrometry, and phenacetin and its primary metabolite, acetaminophen, were monitored. After intravenous dosing, all groups showed similar exposure of phenacetin irrespective of genotype. After oral dosing at 15 mg/kg, the exposure of phenacetin in CC and CT dogs was similar, but phenacetin exposure was 2-fold greater in TT dogs. Exposure of the metabolite, acetaminophen, was similar in all groups; however, the mean acetaminophen/phenacetin ratio in TT dogs was 1.7 times less than that observed in CC dogs. Similar trends between the groups of dogs with respect to phenacetin exposure were also observed after a lower 5 mg/kg p.o. dose of phenacetin; however, a proportionally greater amount of acetaminophen was generated. Although oral exposure of phenacetin was 2-fold higher and acetaminophen exposure was 2-fold lower in CYP1A2-deficient (TT) dogs, these results were considered modest and suggest that phenacetin is not a selective or robust in vivo probe to measure CYP1A2 enzyme activity in the dog. IntroductionCytochrome P450 (P450) enzymes play a significant role in the oxidative metabolism and elimination of xenobiotics and endogenous substances. P450 enzymes have been extensively studied in humans and rodents; however, dogs are commonly used for pharmacological and absorption, distribution, metabolism, and excretion/toxicology studies of new drug candidates, and studies of their P450 enzymes and polymorphisms are few (Tenmizu et al., 2006;Zhou et al., 2010). Although genetic polymorphisms have been reported in the dog, our understanding of their contribution to the interindividual variability in drug pharmacokinetics related to pharmaceutical drug development and veterinary practice is limited (Mise et al., 2004a).The CYP1A2 enzyme is expressed in all mammals with few species differences in function or regulation, and all have very similar amino acid sequences (Parkinson and Ogilvie, 2008). In humans, CYP1A2 polymorphisms in the coding region are rare and only occasionally appear to decrease enzyme activity (Faber et al., 2005). A CYP1A2 polymorphism in beagle dogs has been reported (Tenmizu et al., 2004). The mutation is a single nucleotide polymorphism, CYP1A2 1117 CϾT, which results in an amino acid change from arginine to an early stop codon at position 373 (truncated inactive protein). Pharmacokinetic variability was observed in dogs after administration of 5-(3-methoxyphenyl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)-2-oxo-1,2-d...

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Identification of the novel canine CYP1A2 1117 C>T SNP causing protein deletion

Cited by 41 publications

References 22 publications

Pharmacogenetic and Metabolic Differences Between Dog Breeds: Their Impact on Canine Medicine and the Use of the Dog as a Preclinical Animal Model

Pharmacogenetic and Metabolic Differences Between Dog Breeds: Their Impact on Canine Medicine and the Use of the Dog as a Preclinical Animal Model

Elucidation of the Effects of the CYP1A2 Deficiency Polymorphism in the Metabolism of 4-Cyclohexyl-1-ethyl-7-methylpyrido[2,3-d]pyrimidine-2-(1H)-one (YM-64227), a Phosphodiesterase Type 4 Inhibitor, and Its Metabolites in Dogs

Phenacetin Pharmacokinetics in CYP1A2-Deficient Beagle Dogs

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