Human CYP2C8 Is Post-Transcriptionally Regulated by MicroRNAs 103 and 107 in Human Liver

Zhang, Shuyun; Surapureddi, Sailesh; Coulter, Sherry J.; Ferguson, Stephen S. G.; Goldstein, Joyce A.

doi:10.1124/mol.112.078386

Cited by 66 publications

(50 citation statements)

References 56 publications

(58 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast to numerous studies reporting the importance of genetic polymorphisms that influence CYP2C19 gene expression, the role of miRNAs in its regulation has been under-investigated. Zhang et al [22] reported that miR-103 and miR-107 post-transcriptionally regulate CYP2C8, CYP2C9 and CYP2C19, the only published study available in the literature. Compared to their study, our in silico approach was unable to identify putative miR-103 and miR-107 targeting sites in the 3′-UTR of CYP2C19.…”

Section: Discussionmentioning

confidence: 99%

“…MiRNAs have been shown to affect the expression of many DMEs, including CYP1B1 [18],CYP2E1 [19], CYP3A4 [20] and SULT1A1 [21]. In the case of CYP2C19, two miRNA binding sites were identified within its 3′-UTR that interacted with miR-103 or miR-107 [22]. Transfection of ectopic miR-103 and miR-107 into human hepatocytes resulted in decreased CYP2C19 expression, suggesting that altered miRNA levels among humans could contribute to the inter-individual variability of CYP2C19 expression.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

MicroRNA hsa-miR-29a-3p modulates CYP2C19 in human liver cells

Green

Tolleson

et al. 2015

Biochemical Pharmacology

View full text Add to dashboard Cite

Cytochrome P450 2C19 (CYP2C19) is involved in the metabolism of many drugs. Extensive studies have demonstrated that genetic variants and endogenous and environmental factors play important roles in the expression of CYP2C19. However, the role of microRNAs (miRNAs) in controlling CYP2C19 expression has not been investigated completely. In the present study, we performed in silico analysis to rank putative miRNA/CYP2C19 hybrids with regards to the predicted stabilities of their duplexes and then we applied a series of biochemical and molecular assays to elucidate the underlying functional mechanisms for the regulation of CYP2C19 by miRNAs. In silico analysis indicated that hsa-miR-23a-3p and hsa-miR-29a-3p target the coding region of CYP2C19 with hybrid stabilities of −27.5 kcal/mol and −23.3 kcal/mol, respectively. RNA electrophoresis mobility shift assays showed that both hsa-miR-23a-3p and hsa-miR-29a-3p miRNAs were able to bind directly to their cognate targets in the CYP2C19 transcript. Further, a significant inverse correlation was found between chemically-induced up-regulation of hsamiR-29a-3p and CYP2C19 expression in HepaRG cells. In addition, inverse correlations were also observed in human liver tissue samples between the level of CYP2C19 mRNA expression and both hsa-miR-23a-3p and hsa-miR-29a-3p levels. All these results demonstrated the suppressing role of hsa-miR-29a-3p on CYP2C19 expression.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MicroRNA hsa-miR-29a-3p modulates CYP2C19 in human liver cells

Green

Tolleson

et al. 2015

Biochemical Pharmacology

View full text Add to dashboard Cite

show abstract

“…Regarding gene expression modulations, hepatic expression of human P450 2C genes is constitutively regulated by a number of liver transcription factors (Jover et al, 1998;Bort et al, 2004;Ferguson et al, 2005;Kamiyama et al, 2007;Wortham et al, 2007;Surapureddi et al, 2008). The human P450 2C8 gene has been post-transcriptionally regulated by microRNAs (Zhang et al, 2012). Investigating the transcriptional regulation of marmoset P450 2C19, which is important for drug metabolism as a functional counterpart of both human P450 2C9 and 2C19, is of great interest.…”

Section: Discussionmentioning

confidence: 99%

Novel Marmoset Cytochrome P450 2C19 in Livers Efficiently Metabolizes Human P450 2C9 and 2C19 Substrates,S-Warfarin, Tolbutamide, Flurbiprofen, and Omeprazole

et al. 2015

View full text Add to dashboard Cite

The common marmoset (Callithrix jacchus), a small New World monkey, has the potential for use in human drug development due to its evolutionary closeness to humans. Four novel cDNAs, encoding cytochrome P450 (P450) 2C18, 2C19, 2C58, and 2C76, were cloned from marmoset livers to characterize P450 2C molecular properties, including previously reported P450 2C8. The deduced amino acid sequence showed high sequence identities (>86%) with those of human P450 2Cs, except for marmoset P450 2C76, which has a low sequence identity (∼70%) with any human P450 2Cs. Phylogenetic analysis showed that marmoset P450 2Cs were more closely clustered with those of humans and macaques than other species investigated. Quantitative polymerase chain reaction analysis showed that all of the marmoset P450 2C mRNAs were predominantly expressed in liver as opposed to the other tissues tested. Marmoset P450 2C proteins were detected in liver by immunoblotting using antibodies against human P450 2Cs. Among marmoset P450 2Cs heterologously expressed in Escherichia coli, marmoset P450 2C19 efficiently catalyzed human P450 2C substrates, S-warfarin, diclofenac, tolbutamide, flurbiprofen, and omeprazole. Marmoset P450 2C19 had high V max and low K m values for S-warfarin 7-hydroxylation that were comparable to those in human liver microsomes, indicating warfarin stereoselectivity similar to findings in humans. Faster in vivo S-warfarin clearance than R-warfarin after intravenous administration of racemic warfarin (0.2 mg/kg) to marmosets was consistent with the in vitro kinetic parameters. These results indicated that marmoset P450 2C enzymes had functional characteristics similar to those of humans, and that P450 2C-dependent metabolic properties are likewise similar between marmosets and humans.

show abstract

“…Previously, we found that miRNAs regulate human xenobioticmetabolizing enzymes such as CYP1B1 (Tsuchiya et al, 2006) and CYP2A6 (Nakano et al, 2015). Another research group reported that human CYP2C8 is also regulated by miRNAs (Zhang et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Single-Nucleotide Polymorphisms in Cytochrome P450 2E1 (CYP2E1) 3′-Untranslated Region Affect the Regulation of CYP2E1 by miR-570

et al. 2015

View full text Add to dashboard Cite

Human cytochrome P450 2E1 (CYP2E1) catalyzes the metabolism of numerous xenobiotics, including acetaminophen and ethanol. CYP2E1 expression is known to be extensively regulated by posttranscriptional and post-translational mechanisms. A previous study had reported that a single-nucleotide polymorphism (SNP) 1561A>G in the 39-untranslated region (39-UTR) of CYP2E1 leads to a decreased CYP2E1 mRNA level in human peripheral blood mononuclear cells. In this study, we examined the possibility that microRNA(s) (miR) may be involved in the SNP-mediated modulation of CYP2E1 expression. Genotyping and sequencing analyses revealed that another SNP, 1556T>A, in the 39-UTR was in complete linkage disequilibrium with the SNP 1561A>G. We termed the alleles with 1556T and 1561A or 1556A and 1561G haplotype I or II, respectively. A luciferase assay revealed that miR-570 recognizes the CYP2E1 39-UTR of haplotype I but not haplotype II. Human embryonic kidney 293 (HEK293) cell lines stably expressing human CYP2E1 that included the 39-UTR of haplotype I or II (HEK/2E1(I) or HEK/2E1(II) cells, respectively) were established. Overexpression of miR-570 significantly decreased the CYP2E1 protein level in the HEK/2E1(I) cells but not in the HEK/2E1(II) cells. In seven human livers with diplotype I/I, the CYP2E1 protein levels were inversely correlated with the miR-570 levels, but no relationship was observed in 25 human livers with diplotypes I/II and II/II. Collectively, it was demonstrated that human CYP2E1 was regulated by miR-570 in a genotypedependent manner. This report describes the first proof that SNP in 39-UTR of human P450 affects binding of miRNA to modulate the expression in the liver.

show abstract

Human CYP2C8 Is Post-Transcriptionally Regulated by MicroRNAs 103 and 107 in Human Liver

Cited by 66 publications

References 56 publications

MicroRNA hsa-miR-29a-3p modulates CYP2C19 in human liver cells

MicroRNA hsa-miR-29a-3p modulates CYP2C19 in human liver cells

Novel Marmoset Cytochrome P450 2C19 in Livers Efficiently Metabolizes Human P450 2C9 and 2C19 Substrates,S-Warfarin, Tolbutamide, Flurbiprofen, and Omeprazole

Single-Nucleotide Polymorphisms in Cytochrome P450 2E1 (CYP2E1) 3′-Untranslated Region Affect the Regulation of CYP2E1 by miR-570

Contact Info

Product

Resources

About