Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and alternative-splice variants

Nelson, David R.; Zeldin, Darryl C.; Hoffman, Susan M.G.; Maltais, Lois J.; Wain, Hester; Nebert, Daniel W.

doi:10.1097/00008571-200401000-00001

Cited by 848 publications

(680 citation statements)

References 44 publications

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“…The alleles CYP2D6*10 and *41 give rise to significantly decreased enzyme activity. However, the allele frequency of CYP2D6*10 is 1-2% in Caucasians, this allele variant is typical in the Asian population with an allele frequency of 33-43% [10]. CYP2D6*10 has a 100C>T SNP leading to the instability of the enzyme protein [11].…”

Section: Introductionmentioning

confidence: 99%

Is CYP2D6 phenotype predictable from CYP2D6 genotype?

Kiss

Tóth

Juhasz

et al. 2018

Microchemical Journal

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Hungary Highlights• CYP2D6 genotype-based phenotype estimation is of particular importance to personalized medication strategy.• The non-sequencing genotyping platform identified the most frequent CYP2D6 allelic variants (in 67% of the donors).• The gain-of-function mutation (-1584C>G) could explain the underestimation of CYP2D6 genotype-based prediction.• Some rare loss-of-function mutations that were not captured, could result in overestimation of CYP2D6 activity prediction.• CYP2D6 phenotype overestimation may also come from external factors modifying CYP2D6 activity or altering hepatic function.• A comprehensive genotyping and consideration of phenoconversion can improve the genotype-based CYP2D6 phenotype prediction. 2 AbstractGenetic polymorphism of cytochrome P450s results in clinically significant modifications in patients' drug metabolizing capacities. CYP2D6 has a crucial role in the elimination of several clinically important drugs (antiarrhythmics, beta-adrenergic blockers, psychopharmacons and analgesics); however, the prediction of the phenotypic appearance of CYP2D6 is a challenge. Since single nucleotide polymorphisms and gene copy number variations (gene deletion and multiplication) frequently occur in CYP2D6 gene, CYP2D6 activity particularly depends on the genetic factors.Microsomal CYP2D6 activities (dextromethorphan O-demethylation) and CYP2D6 genotypes for the most frequent allelic variants (CYP2D6*3, *4, *5, *6, *10, *41 and duplication) were determined in 128 human liver samples derived from Hungarian organ donors. Substantial inter-individual variations were observed in CYP2D6 metabolic activities that were successfully predicted from the CYP2D6 genotypes in 67% of the donors. The underestimation of CYP2D6 phenotypes in 12.5% of the donors was assumed to be originated from the overlapping ranges of CYP2D6 activity among similar diplotypes or from the presence of -1584C>G in the promoter region evoking increased transcription of the wild-type CYP2D6 allele. In an appreciable number of donors (20.3%), the genotype-based CYP2D6 phenotype prediction was overestimated because of the rare CYP2D6 allelic variants which were not included in our genotyping platform or some external factors that could alter CYP2D6 activity (medication with CYP2D6 substrate/inhibitor) and hepatic function (Augmentin therapy, chronic alcohol consumption).In conclusion, CYP2D6 genotyping for the most frequent allelic variants was able to reliably predict CYP2D6 phenotypes in most donors; however, the external factors modifying the phenotypic appearance of CYP2D6 had to be taken into account. Personalized medication strategy should include monitoring of CYP2D6 genotype in a more comprehensive manner 3 and should take external factors into consideration for an appropriate prediction of CYP2D6 metabolizing capacity.

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Section: Introductionmentioning

confidence: 99%

Is CYP2D6 phenotype predictable from CYP2D6 genotype?

Kiss

Tóth

Juhasz

et al. 2018

Microchemical Journal

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“…The modulation of a cytochrome P-450 protein by CC12 could be the basis for this drug's antianalgesic action, since a P-450 pathway has been implicated in supraspinal opioid analgesic signaling (Vaughan et al, 1997). Unpublished preliminary results confirm that CC12 inhibits some forms of cytochrome P-450, but the large number of P-450 proteins (Nelson et al, 2004) and the analgesic (vs. anti-analgesic) activity of some P-450 inhibitors (Ho et al, 1978,Lehman andPeterson, 1978) present challenges to establishing this mechanism of action. The presently-described anti-analgesic actions of CC12 will help elucidate the mechanisms by which improgan, as well as other analgesics, act to reduce nociceptive transmission.…”

Section: Discussionmentioning

confidence: 91%

CC12, a high-affinity ligand for [3H]cimetidine binding, is an improgan antagonist

Hough

Nalwalk

Phillips³

et al. 2007

Neuropharmacology

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SummaryImprogan, a chemical congener of cimetidine, is a highly effective non-opioid analgesic when injected into the CNS. Despite extensive characterization, neither the improgan receptor, nor a pharmacological antagonist of improgan has been previously described. Presently, the specific binding of 3 H-cimetidine (3HCIM) in brain fractions was used to discover 4(5)-((4-iodobenzyl) thiomethyl)-1H-imidazole, which behaved in vivo as the first improgan antagonist. The synthesis and pharmacological properties of this drug (named CC12) are described herein. In rats, CC12 (50 -500 nmol, icv) produced dose-dependent inhibition of improgan (200 -400 nmol) antinociception on the tail flick and hot plate tests. When given alone to rats, CC12 had no effects on nociceptive latencies, or on other observable behavioral or motor functions. Maximal inhibitory effects of CC12 (500 nmol) were fully surmounted with a large icv dose of improgan (800 nmol), demonstrating competitive antagonism. In mice, CC12 (200-400 nmol, icv) behaved as a partial agonist, producing incomplete improgan antagonism, but also limited antinociception when given alone. Radioligand binding, receptor autoradiography, and electrophysiology experiments showed that CC12's antagonist properties are not explained by activity at 25 sites relevant to analgesia, including known receptors for cannabinoids, opioids or histamine. The use of CC12 as an improgan antagonist will facilitate the characterization of improgan analgesia. Furthermore, because CC12 was also found presently to inhibit opioid and cannabinoid antinociception, it is suggested that this drug modifies a biochemical mechanism shared by several classes of analgesics. Elucidation of this mechanism will enhance understanding of the biochemistry of pain relief.

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“…of mouse P450 expression and function can provide insight into P450 expression and function in humans (50). Thus, to understand the association between loss of ABCB6 expression and the pattern of P450 expression in humans, we evaluated P450 expression in human hepatoma cells (Hep3B and Huh7) deficient in endogenous ABCB6.…”

Section: Journal Of Biological Chemistry 7877mentioning

confidence: 99%

Functional Coupling of ATP-binding Cassette Transporter Abcb6 to Cytochrome P450 Expression and Activity in Liver

Chavan¹,

Li²,

Tessman³

et al. 2015

Journal of Biological Chemistry

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Background: Physiological signals that negatively regulate CYP450s are not well understood. Results: Loss of Abcb6 in mice results in suppression of CYP450 activity. Conclusion: Suppression of P450 activity in Abcb6 deficiency may result from altered endogenous metabolites involved in maintaining homeostasis. Significance: Understanding metabolite alterations in Abcb6 deficiency should help understand the physiological signals and the mechanisms involved in negative regulation of P450s.

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Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and alternative-splice variants

Cited by 848 publications

References 44 publications

Is CYP2D6 phenotype predictable from CYP2D6 genotype?

Is CYP2D6 phenotype predictable from CYP2D6 genotype?

CC12, a high-affinity ligand for [3H]cimetidine binding, is an improgan antagonist

Functional Coupling of ATP-binding Cassette Transporter Abcb6 to Cytochrome P450 Expression and Activity in Liver

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