Deciphering pyrethroid resistance in Cx. pipiens (L): Implications of cytochrome P450; expression profiling and regulatory microRNA

Abstract Insecticide-based interventions, notably long-lasting insecticidal nets (LLINs), against mosquito vectors of malaria are currently threatened by pyrethroid resistance. Here, we contrasted RNAseq-based gene expression profiling of laboratory resistant (FUMOZ) and susceptible (FANG) strains of the major malaria vector Anopheles funestus. Cytochrome P450 genes were the predominant over-expressed detoxification genes in FUMOZ, with high expression of the duplicated CYP6P9a (fold-change of 82.23 versus FANG) and CYP6P9b (FC 11.15). Other over-expressed P450s belonged to the same cluster of P450s corresponding to the resistance to pyrethroid 1 (rp1) QTL on chromosome 2R. Several Epsilon class glutathione s-transferases were also over-expressed in FUMOZ, as was the ATP-binding cassette transporter AFUN019220 (ABCA) which also exhibited between-strain alternative splicing events at exon 7. Significant differences in SNP frequencies between strains occurred in resistance QTLs rp1 (CYP6P9a/b, CYP6AA1), rp2 on chromosome 2 L (CYP6Z1, CYP6M7, CYP6Z3) and rp3 on chromosome 3R (CYP9J5, CYP9J4 and CYP9J3). Differences were also detected in CYP4G17 and CYP4G16 genes on the X chromosome, both of which are associated with cuticular resistance in An. gambiae. A close analysis of nonsynonymous diversity at the CYP6P9a/b loci revealed a drastic loss of diversity in FUMOZ with only a single polymorphism and 2 haplotypes vs 18 substitutions and 8 haplotypes in FANG. By contrast, a lowly expressed cytochrome P450 (CYP4C36) did not exhibit diversity differences between strains. We also detected the known pyrethroid resistance conferring amino acid change N384S in CYP6P9b. This study further elucidates the molecular bases of resistance in An. funestus, informing strategies to better manage widespread resistance across Africa.

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Faculty Opinions recommendation of Acute doxorubicin toxicity differentially alters cytochrome P450 expression and arachidonic acid metabolism in rat kidney and liver.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.10961956.11897054 ◽

2011 ◽

Author(s):

John Imig

Keyword(s):

Arachidonic Acid ◽

Cytochrome P450 ◽

Acid Metabolism ◽

Rat Kidney ◽

Arachidonic Acid Metabolism ◽

Doxorubicin Toxicity ◽

P450 Expression

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Escalation of Pyrethroid Resistance in the Malaria Vector Anopheles funestus Induces a Loss of Efficacy of Piperonyl Butoxide–Based Insecticide-Treated Nets in Mozambique

The Journal of Infectious Diseases ◽

10.1093/infdis/jiz139 ◽

2019 ◽

Vol 220 (3) ◽

pp. 467-475 ◽

Cited By ~ 16

Author(s):

Jacob M Riveron ◽

Silvie Huijben ◽

Williams Tchapga ◽

Magellan Tchouakui ◽

Murielle J Wondji ◽

...

Keyword(s):

Cytochrome P450 ◽

Pyrethroid Resistance ◽

Anopheles Funestus ◽

Resistance Mechanisms ◽

Piperonyl Butoxide ◽

Insecticide Treated Nets ◽

Molecular Analyses ◽

Cytochrome P450 Genes ◽

High Degree ◽

Long Lasting Insecticidal Nets

Abstract Background Insecticide resistance poses a serious threat to insecticide-based interventions in Africa. There is a fear that resistance escalation could jeopardize malaria control efforts. Monitoring of cases of aggravation of resistance intensity and its impact on the efficacy of control tools is crucial to predict consequences of resistance. Methods The resistance levels of an Anopheles funestus population from Palmeira, southern Mozambique, were characterized and their impact on the efficacy of various insecticide-treated nets established. Results A dramatic loss of efficacy of all long-lasting insecticidal nets (LLINs), including piperonyl butoxide (PBO)–based nets (Olyset Plus), was observed. This An. funestus population consistently (2016, 2017, and 2018) exhibited a high degree of pyrethroid resistance. Molecular analyses revealed that this resistance escalation was associated with a massive overexpression of the duplicated cytochrome P450 genes CYP6P9a and CYP6P9b, and also the fixation of the resistance CYP6P9a_R allele in this population in 2016 (100%) in contrast to 2002 (5%). However, the low recovery of susceptibility after PBO synergist assay suggests that other resistance mechanisms could be involved. Conclusions The loss of efficacy of pyrethroid-based LLINs with and without PBO is a concern for the effectiveness of insecticide-based interventions, and action should be taken to prevent the spread of such super-resistance.

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The Effect of Chronic Iloperidone Treatment on Cytochrome P450 Expression and Activity in the Rat Liver: Involvement of Neuroendocrine Mechanisms

International Journal of Molecular Sciences ◽

10.3390/ijms22168447 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8447

Author(s):

Przemysław J. Danek ◽

Wojciech Kuban ◽

Władysława A. Daniel

Keyword(s):

Cytochrome P450 ◽

Rat Liver ◽

Combined Treatment ◽

Pharmacological Therapy ◽

Mental Wellbeing ◽

Cyp Enzymes ◽

P450 Expression ◽

Male Wistar Rats ◽

Expression And Activity

In order to achieve a desired therapeutic effect in schizophrenia patients and to maintain their mental wellbeing, pharmacological therapy needs to be continued for a long time, usually from the onset of symptoms and for the rest of the patients’ lives. The aim of our present research is to find out the in vivo effect of chronic treatment with atypical neuroleptic iloperidone on the expression and activity of cytochrome P450 (CYP) in rat liver. Male Wistar rats received a once-daily intraperitoneal injection of iloperidone (1 mg/kg) for a period of two weeks. Twenty-four hours after the last dose, livers were excised to study cytochrome P450 expression (mRNA and protein) and activity, pituitaries were isolated to determine growth hormone-releasing hormone (GHRH), and blood was collected for measuring serum concentrations of hormones and interleukin. The results showed a broad spectrum of changes in the expression and activity of liver CYP enzymes, which are important for drug metabolism (CYP1A, CYP2B, CYP2C, and CYP3A) and xenobiotic toxicity (CYP2E1). Iloperidone decreased the expression and activity of CYP1A2, CP2B1/2, CYP2C11, and CYP3A1/2 enzymes but increased that of CYP2E1. The CYP2C6 enzyme remained unchanged. At the same time, the level of GHRH, GH, and corticosterone decreased while that of T3 increased, with no changes in IL-2 and IL-6. The presented results indicate neuroendocrine regulation of the investigated CYP enzymes during chronic iloperidone treatment and suggest a possibility of pharmacokinetic/metabolic interactions produced by the neuroleptic during prolonged combined treatment with drugs that are substrates of iloperidone-affected CYP enzymes.

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