A genetic approach to the prediction of drug side effects: bleomycin induces concordant phenotypes in mice of the collaborative cross

Gelinas, Richard; Chesler, Elissa J.; Vasconcelos, Daphne; Miller, Darla R.; Yuan, Yue; Wang, Kai; Galas, David J.

doi:10.2147/pgpm.s22475

Cited by 9 publications

(5 citation statements)

References 22 publications

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“…As of today, multidisciplinary studies using the CC lines at our laboratory and others has already demonstrated unprecedented power for high‐resolution QTL mapping (~1 Mb) by phenotyping a relatively modest number of CC lines (~30 lines) with sufficient replication …”

Section: Introductionmentioning

confidence: 99%

Mapping novel genetic loci associated with female liver weight variations using Collaborative Cross mice

Atamni

Botzman

Mott

et al. 2018

Anim Models and Exp Med

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Background Liver weight is a complex trait, controlled by polygenic factors and differs within populations. Dissecting the genetic architecture underlying these variations will facilitate the search for key role candidate genes involved directly in the hepatomegaly process and indirectly involved in related diseases etiology. Methods Liver weight of 506 mice generated from 39 different Collaborative Cross ( CC ) lines with both sexes at age 20 weeks old was determined using an electronic balance. Genomic DNA of the CC lines was genotyped with high‐density single nucleotide polymorphic markers. Results Statistical analysis revealed a significant ( P < 0.05) variation of liver weight between the CC lines, with broad sense heritability ( H 2 ) of 0.32 and genetic coefficient of variation ( CV G ) of 0.28. Subsequently, quantitative trait locus ( QTL ) mapping was performed, and results showed a significant QTL only for females on chromosome 8 at genomic interval 88.61‐93.38 Mb (4.77 Mb). Three suggestive QTL were mapped at chromosomes 4, 12 and 13. The four QTL were designated as LWL 1‐ LWL 4 referring to liver weight loci 1‐4 on chromosomes 8, 4, 12 and 13, respectively. Conclusion To our knowledge, this report presents, for the first time, the utilization of the CC for mapping QTL associated with baseline liver weight in mice. Our findings demonstrate that liver weight is a complex trait controlled by multiple genetic factors that differ significantly between sexes.

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Section: Introductionmentioning

confidence: 99%

Mapping novel genetic loci associated with female liver weight variations using Collaborative Cross mice

Atamni

Botzman

Mott

et al. 2018

Anim Models and Exp Med

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“…While the CC population has been proven phenotypically diverse, the extent to which drug disposition varies across these strains is still largely unknown (Rusyn et al, 2010 ; Gelinas et al, 2011 ; Frick et al, 2013 ). One of the many mechanisms through which variation in drug disposition can arise is the biotransformation of drugs in the liver.…”

Section: Introductionmentioning

confidence: 99%

Dissecting the Effect of Genetic Variation on the Hepatic Expression of Drug Disposition Genes across the Collaborative Cross Mouse Strains

et al. 2016

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A central challenge in pharmaceutical research is to investigate genetic variation in response to drugs. The Collaborative Cross (CC) mouse reference population is a promising model for pharmacogenomic studies because of its large amount of genetic variation, genetic reproducibility, and dense recombination sites. While the CC lines are phenotypically diverse, their genetic diversity in drug disposition processes, such as detoxification reactions, is still largely uncharacterized. Here we systematically measured RNA-sequencing expression profiles from livers of 29 CC lines under baseline conditions. We then leveraged a reference collection of metabolic biotransformation pathways to map potential relations between drugs and their underlying expression quantitative trait loci (eQTLs). By applying this approach on proximal eQTLs, including eQTLs acting on the overall expression of genes and on the expression of particular transcript isoforms, we were able to construct the organization of hepatic eQTL-drug connectivity across the CC population. The analysis revealed a substantial impact of genetic variation acting on drug biotransformation, allowed mapping of potential joint genetic effects in the context of individual drugs, and demonstrated crosstalk between drug metabolism and lipid metabolism. Our findings provide a resource for investigating drug disposition in the CC strains, and offer a new paradigm for integrating biotransformation reactions to corresponding variations in DNA sequences.

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“…Therefore BLM causes DNA cleavage and fragmentation leading finally to cellular apoptosis, necrosis and deaths. However, the antineoplastic drug bleomycin is now a second-line therapy for certain solid tumors (6), it causes several side effects such as nausea, vomiting, fever (often with rigors) and occasional allergic type reactions, but pulmonary toxicity are is a major adverse effect (7). This side effect was widely studied in animal models and it is related to oxidant-induced inflammatory and fibrotic lesions in the lung through oxidative stress (5,8).…”

Section: Introductionmentioning

confidence: 99%

Epicatechin enhances anti-proliferative effect of bleomycin in ovarian cancer cell

2013

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Background: Bleomycin (BLM) is an anti-cancer drug widely used in the treatment of cancer. BLM causes several side effects related to DNA and cellular damage. The aim of this study was investigated the effects of tea polyphenol epicatechin on anti-proliferative effects induced by bleomycin in human normal skin and human ovarian cancer cells. Materials and Methods: Human ovarian cancer cell (SKOV-3) and human nonmalignant fibroblast cell (HFFF2) were treated with epicatechin at various concentrations (10, 25 and 50 µM) and BLM alone and with their combinations, further their effects on cell viability were evaluated. Results: The combined treatment of epicatechin with BLM enhanced significantly inhibition of cell growth in comparison to BLM alone in cancer cell. Epicatechin enhanced significantly cytotoxicity induced by BLM with 83% at dose 50 µM, while it was 92% in BLM-treated cells. Epicatechin was not showed any cytotoxicity on HFFF2 cells. Conclusion: Study suggests that epicatechin chemosensitize the ovarian cancer cell to BLM-induced growth inhibition without any toxicity on normal cell.

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A genetic approach to the prediction of drug side effects: bleomycin induces concordant phenotypes in mice of the collaborative cross

Cited by 9 publications

References 22 publications

Mapping novel genetic loci associated with female liver weight variations using Collaborative Cross mice

Mapping novel genetic loci associated with female liver weight variations using Collaborative Cross mice

Dissecting the Effect of Genetic Variation on the Hepatic Expression of Drug Disposition Genes across the Collaborative Cross Mouse Strains

Epicatechin enhances anti-proliferative effect of bleomycin in ovarian cancer cell

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