Association of cytochrome P450 2D15 (CYP2D15) nonsynonymous polymorphisms and exon 3 deleted RNA splice variant with CYP2D15 protein content and enzyme function in dog liver microsomes

Jimenez, Tania Perez; Zhu, Zhaohui; Court, Michael H.

doi:10.1111/jvp.13113

Cited by 5 publications

(3 citation statements)

References 22 publications

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“…The likelihood of antimicrobial, antiviral and anti-inflammatory effects of the studied substances has been associated with inhibition of aspulvinone dimethylallyltransferase [70,71]. The results also revealed the ability of LAS-252 to affect the biotransformation process by using CYP2D15, which is a human orthologue (CYP2D6), leading to amino acid changes in canine liver microsomes [72]. According to the results obtained, this compound can influence neuromuscular conduction regulated by cholinergic activity through a direct stimulatory effect on nicotinic alpha4beta4 receptors responsible for neurotransmission in parts of the central and peripheral nervous system.…”

Section: Discussionmentioning

confidence: 87%

Computer‐aided evaluation of targets and biological activity spectra for new piperidine derivatives

Khaiitova

2023

J CLIN MED KAZ

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Background: The unique ability of piperidine to combine with various molecular fragments makes it possible to use its chemical structure to create new drugs with potential pharmacological effects. However, preliminary studies are required to predict the activity of new compounds in order to determine the direction of further preclinical studies. Aim: This study aims at determining the potential targets and spectrum of biological activity of new piperidine derivatives by the in silico method. Material and methods: Prediction of the effects on targets and the spectrum of biological activity of three new piperidine derivatives synthesized at the Bekturov Institute of Chemical Sciences JSC was analyzed in this study. The chemical structures of these compounds were studied in silico using the web tool SwissTargetPrediction to identify the most likely protein targets. PASS (Prediction of Activity Spectra for Substances) online tool was used to predict the possible pharmacological activity of the studied compounds. Results: New modified piperidine derivatives are able to affect different enzymes, receptors, transport systems, voltage-gated ion channels, thereby providing a wide range of biological activities applicable in various fields of medicine. These substances represent interest in the treatment of cancer, central nervous system diseases, as local anesthetic, antiarrhythmic and antimicrobial agents, and are promising for pharmacological activity demonstration in preclinical studies. Conclusion: A comprehensive analysis of the above results leads to the conclusion that the compounds under study should be considered as potential substances for the design of new highly effective medicinal agents with a wide range of practical applications.

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Section: Discussionmentioning

confidence: 87%

Computer‐aided evaluation of targets and biological activity spectra for new piperidine derivatives

Khaiitova

2023

J CLIN MED KAZ

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“…In marmosets, CYP2D8 (expressed in liver and extrahepatic tissues) appears to have substrate specificities different from those of marmoset CYP2D6 (expressed predominantly in liver), which is not unexpected, given that only minor amino acid changes can alter the substrate specificity of human CYP2D6 (Uehara et al, 2015). In dogs, the Ile109Val substitution decreases the functionality of CYP2D15 (Jimenez et al, 2023), and this residue (Ile109) is conserved in tree shrew CYP2D8a but not in CYP2D8b (Fig. 1).…”

Section: Discussionmentioning

confidence: 93%

Novel Tree Shrew Cytochrome P450 2Ds (CYP2D8a and CYP2D8b) Are Functional Drug-Metabolizing Enzymes that Metabolize Bufuralol and Dextromethorphan

Ushirozako,

Murayama,

Tsukiyama-Kohara

et al. 2024

Drug Metab Dispos

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Tree shrews are a non-primate species used in a range of biomedical studies. Recent genome analysis of tree shrews found that the sequence identities and the numbers of genes of cytochromes P450 (CYP or P450s), an important family of drug-metabolizing enzymes, are similar to those of humans. However, tree shrew P450s have not yet been sufficiently identified and analyzed. In this study, novel CYP2D8a and CYP2D8b cDNAs were isolated from tree shrew liver and were characterized, along with human CYP2D6, dog CYP2D15, and pig CYP2D25. The amino acid sequences of these tree shrew CYP2Ds were 75-78 % identical to human CYP2D6, and phylogenetic analysis showed that they were more closely related to human CYP2D6 than rat CYP2Ds, similar to dog and pig CYP2Ds.For tree shrew CYP2D8b, two additional transcripts were isolated that contained different patterns of deletion. The gene and genome structures of CYP2Ds are generally similar in dogs, humans, pigs, and tree shrews. Tree shrew CYP2D8a mRNA was most abundantly expressed in liver, among the tissue types analyzed, similar to dog CYP2D15 and pig CYP2D25 mRNAs. Tree shrew CYP2D8b mRNA was also expressed in liver, but at a level 7.3-fold lower than CYP2D8a mRNA. Liver microsomes and recombinant protein of both tree shrew CYP2Ds metabolized bufuralol and dextromethorphan, selective substrates of human CYP2D6, but the activity level of CYP2D8a greatly exceeded that of CYP2D8b. These results suggest that tree shrew CYP2D8a and CYP2D8b are functional drug-metabolizing enzymes, of which CYP2D8a is the major CYP2D in liver.

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“…It is possible that the outlier was homozygous for a CYP2D15 mutation associated with reduced activity while the littermate was heterozygous. 19 While dogs were not genotyped for any known CYP mutations in this study, it does show the sensitivity of the probe to detect differences in CYP activity, which may be helpful in identifying new clinically relevant genotypes.…”

Section: Spearman Correlation Coefficient (P Value)mentioning

confidence: 99%

Validation of a bupropion, dextromethorphan, and omeprazole cocktail for simultaneous phenotyping of cytochrome P450 2B11, 2D15, and 3A12 activities in dogs

Martinez,

Jimenez,

Court

2024

ajvr

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OBJECTIVE Develop a cytochrome P450 (CYP) phenotyping cocktail for dogs using specific substrates for hepatic P450 enzymes CYP2B11, CYP2D15, and CYP3A12 and determine whether alternative sampling methods (saliva and urine) or single time point samples could be used instead of multiple blood sampling. ANIMALS 12 healthy client-owned dogs (8 females and 4 males) from February 2019 to May 2019. METHODS In a randomized crossover study, dogs received oral administration of the probe drug bupropion (75 mg), dextromethorphan (30 mg), or omeprazole (40 mg) alone or as a 3-drug combination (Program in Individualized Medicine [PrIMe] cocktail) to evaluate simultaneous phenotyping of CYP2B11, CYP2D15, and CYP3A12. Pharmacokinetic profiles for the probe drugs and metabolites were determined using plasma, saliva, and urine. Dogs received probe drugs alone or combined. Pharmacokinetic profiles up to 6 hours postdose for the probe drugs and metabolites were determined using plasma, saliva, and urine. RESULTS The PrIMe cocktail was well tolerated. There was no statistically significant interaction between the probe drugs when administered together. Single time point plasma metabolic ratios at 4 hours postdose for all probe drugs strongly correlated with the corresponding area under the plasma concentration-versus-time curve (AUC) ratios. Saliva AUC metabolic ratios for CYP3A12 and CYP2D15 and 6-hour urine for CYP2B11 and CYP2D15 were correlated with plasma AUC ratios. CONCLUSIONS The PrIMe cocktail can be used for simultaneous CYP phenotyping using plasma 4-hour single time point sample metabolic ratios. Saliva and urine sampling are suitable for specific CYPs. CLINICAL RELEVANCE The PrIMe cocktail has potential as a useful tool in dogs to detect clinically important CYP-mediated drug-drug interactions, identify novel pharmacogenes, determine the drug-metabolizing phenotype of individual dogs, aid in individualized dose selection, and evaluate the effects of various physiological states on drug metabolism.

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Association of cytochrome P450 2D15 (CYP2D15) nonsynonymous polymorphisms and exon 3 deleted RNA splice variant with CYP2D15 protein content and enzyme function in dog liver microsomes

Cited by 5 publications

References 22 publications

Computer‐aided evaluation of targets and biological activity spectra for new piperidine derivatives

Computer‐aided evaluation of targets and biological activity spectra for new piperidine derivatives

Novel Tree Shrew Cytochrome P450 2Ds (CYP2D8a and CYP2D8b) Are Functional Drug-Metabolizing Enzymes that Metabolize Bufuralol and Dextromethorphan

Validation of a bupropion, dextromethorphan, and omeprazole cocktail for simultaneous phenotyping of cytochrome P450 2B11, 2D15, and 3A12 activities in dogs

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