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In silico identification of microRNAs predicted to regulate the drug metabolizing cytochrome P450 genes.

ABSTRACT: OBJECTIVE:Cytochrome P450 (CYP) enzymes exhibit high interindividual variability that is not completely explained by known environmental and genetic factors. To further understand this variability, we hypothesized that microRNAs (miRNAs) may regulate CYP expression. METHODS:MiRNA identification algorithms were used to identify the miRNAs that are predicted to regulate twelve major drug metabolizing CYPs and to identify polymorphisms in CYP mRNA 3'-UTRs that are predicted to interfere with normal mRNA-miRNA interactions. RESULTS:All twelve CYPs were predicted to be targets of miRNAs. Additionally, 38 SNPs in CYP mRNA 3'-UTRs were predicted to interfere with miRNA targeting of mRNAs. These predicted miRNAs and SNPs are candidates for future in vitro studies focused on understanding the molecular regulation of these CYP genes. CONCLUSION:These in silico results provide strong support for a role of miRNA in the regulation and variability of CYP expression.

SUBMITTER: Ramamoorthy A

PROVIDER: S-EPMC4308728 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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In silico identification of microRNAs predicted to regulate the drug metabolizing cytochrome P450 genes.

Ramamoorthy Anuradha A Skaar Todd C TC

Drug metabolism letters 20110401 2

<h4>Objective</h4>Cytochrome P450 (CYP) enzymes exhibit high interindividual variability that is not completely explained by known environmental and genetic factors. To further understand this variability, we hypothesized that microRNAs (miRNAs) may regulate CYP expression.<h4>Methods</h4>MiRNA identification algorithms were used to identify the miRNAs that are predicted to regulate twelve major drug metabolizing CYPs and to identify polymorphisms in CYP mRNA 3'-UTRs that are predicted to interf ...[more]

PMID: 21457141

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Project description:BackgroundSpinosad is important in pest management strategies of multiple insect pests. However, spinosad resistance is emerging in various pest species. Resistance has in some species been associated with alterations of the target-site receptor, but in others P450s seems to be involved. We test the possible importance of nine cytochrome P450 genes in the spinosad-resistant housefly strain 791spin and investigate the influence of spinosad on P450 expression in four other housefly strains.ResultsSignificant differences in P450 expression of the nine P450 genes in the four strains after spinosad treatment were identified in 40% of cases, most of these as induction. The highly expressed CYP4G2 was induced 6.6-fold in the insecticide susceptible WHO-SRS females, but decreased 2-fold in resistant 791spin males. CYP6G4 was constitutively higher expressed in the resistant strain compared to the susceptible strain. Furthermore, CYP6G4 gene expression was increased in susceptible WHO-SRS flies by spinosad while the expression level did not alter significantly in resistant fly strains. Expression of CYP6A1 and male CYP6D3 was constitutively higher in the resistant strain compared to the susceptible. However, in both cases male expression was higher than female expression.ConclusionCYP4G2, CYP6A1, CYP6D3 and CYP6G4 have expressions patterns approaching the expectations of a hypothesized sex specific spinosad resistance gene. CYP4G2 fit requirements of a spinosad resistance gene best, making it the most likely candidate. The overall high expression level of CYP4G2 throughout the strains also indicates importance of this gene. However, the data on 791spin are not conclusive concerning spinosad resistance and small contributions from multiple P450s with different enzymatic capabilities could be speculated to do the job in 791spin. Differential expression of P450s between sexes is more a rule than an exception. Noteworthy differences between spinosad influenced expression of P450 genes between a field population and established laboratory strains were shown.

Dataset Information

In silico identification of microRNAs predicted to regulate the drug metabolizing cytochrome P450 genes.

Publications

In silico identification of microRNAs predicted to regulate the drug metabolizing cytochrome P450 genes.

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