The role of the efflux carriers Abcg2 and Abcc2 for the hepatobiliary elimination of benzo[a]pyrene and its metabolites in mice

Kranz, J.; Hessel, Stefanie; Aretz, Julia; Seidel, Albrecht; Petzinger, Ernst; Geyer, Joachim; Lampen, Alfonso

doi:10.1016/j.cbi.2014.10.009

Cited by 19 publications

(15 citation statements)

References 38 publications

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“…MRP2 knockdown animal models were used to illustrate the physiological roles of MRP2. MRP2 −/− mice showed decreased hepatobiliary excretion of drugs and toxins as well as their metabolites (33). Also, in MRP2-deficient rats, biliary excretion of (35).…”

Section: Mrp2/cmoatmentioning

confidence: 98%

Multidrug Resistance Proteins (MRPs) and Cancer Therapy

Zhang

Wang

Gupta

et al. 2015

AAPS J

160

114

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Abstract. The ATP-binding cassette (ABC) transporters are members of a protein superfamily that are known to translocate various substrates across membranes, including metabolic products, lipids and sterols, and xenobiotic drugs. Multidrug resistance proteins (MRPs) belong to the subfamily C in the ABC transporter superfamily. MRPs have been implicated in mediating multidrug resistance by actively extruding chemotherapeutic substrates. Moreover, some MRPs are known to be essential in physiological excretory or regulatory pathways. The importance of MRPs in cancer therapy is also implied by their clinical insights. Modulating the function of MRPs to re-sensitize chemotherapeutic agents in cancer therapy shows great promise in cancer therapy; thus, multiple MRP inhibitors have been developed recently. This review article summarizes the structure, distribution, and physiological as well as pharmacological function of MRP1-MRP9 in cancer chemotherapy. Several novel modulators targeting MRPs in cancer therapy are also discussed.

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Section: Mrp2/cmoatmentioning

confidence: 98%

Multidrug Resistance Proteins (MRPs) and Cancer Therapy

Zhang

Wang

Gupta

et al. 2015

AAPS J

160

114

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“…In the body, defense systems against xenobiotics such as BPDE include the activation of detoxifying phase II and III enzymes to prevent further cellular damage; specifically, glutathione S-transferases (GSTs) [14], nicotinamide adenine dinucleotide phosphate (NAD(P)H): quinone oxidoreductase 1 (NQO1), sulfotransferases (SULTs), and multidrug resistance-associated proteins (ABCCs) [15][16][17]. Previous studies showed that the genotoxicity of B[a]P was reduced by phase II enzymes conjugated with B[a]P metabolites and that B[a]P was excreted by ABCCs before BPDE-DNA adducts could form [18][19][20]. Nuclear factor erythroid 2-related factor 2 (Nrf2) and pregnane X receptor (PXR) are important transcriptional factors that regulate the expression of anti-genotoxic phase II detoxification enzymes and phase III transporters [18,19,[21][22][23].…”

Section: Introductionmentioning

confidence: 99%

Modulatory Effects of Silymarin on Benzo[a]pyrene-Induced Hepatotoxicity

Jee

Kim

Sung

2020

IJMS

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Benzo[a]pyrene (B[a]P), a polycyclic aromatic hydrocarbon, is a group 1 carcinogen that introduces mutagenic DNA adducts into the genome. In this study, we investigated the molecular mechanisms underlying the involvement of silymarin in the reduction of DNA adduct formation by B[a]P-7,8-dihydrodiol-9,10-epoxide (BPDE), induced by B[a]P. B[a]P exhibited toxicity in HepG2 cells, whereas co-treatment of the cells with B[a]P and silymarin reduced the formation of BPDE-DNA adducts, thereby increasing cell viability. Determination of the level of major B[a]P metabolites in the treated cells showed that BPDE levels were reduced by silymarin. Nuclear factor erythroid 2-related factor 2 (Nrf2) and pregnane X receptor (PXR) were found to be involved in the activation of detoxifying genes against B[a]P-mediated toxicity. Silymarin did not increase the expression of these major transcription factors, but greatly facilitated their nuclear translocation. In this manner, treatment of HepG2 cells with silymarin modulated detoxification enzymes through NRF2 and PXR to eliminate B[a]P metabolites. Knockdown of Nrf2 abolished the preventive effect of silymarin on BPDE-DNA adduct formation, indicating that activation of the Nrf2 pathway plays a key role in preventing B[a]P-induced genotoxicity. Our results suggest that silymarin has anti-genotoxic effects, as it prevents BPDE-DNA adduct formation by modulating the Nrf2 and PXR signaling pathways.

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“…This expression does not correlate with the even uptake of benzo(a)pyrene observed by fluorescence. Instead, we suggest that this is the combined effect of prolonged diffusion of benzo(a)pyrene into the lipophilic compartments of the microtissue and the slower efflux of metabolites, a process assisted by ABC transporters (Kranz et al, 2014; Luckenbach et al, 2014). Cell death follows this same gradient, with dead cells found primarily at the periphery of treated microtissues.…”

Section: Discussionmentioning

confidence: 88%

A 3D fish liver model for aquatic toxicology: Morphological changes and Cyp1a induction in PLHC-1 microtissues after repeated benzo(a)pyrene exposures

et al. 2017

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To identify the potential environmental impacts of aquatic pollutants, rapid and sensitive screening tools are needed to assess adaptive and toxic responses. This study characterizes a novel fish liver microtissue model, produced with the cell line PLHC-1, as an in vitro aquatic toxicity testing platform. These 3D micro-tissues remain viable and stable throughout the 8-day testing period and relative to 2D monolayers, show increased basal expression of the xenobiotic metabolizing enzyme cytochrome P450 1A (Cyp1a). To evaluate pulsed, low-dose exposures at environmentally relevant concentrations, microtissue responsiveness to the model toxicant benzo(a)pyrene was assessed after single and repeated exposures for determination of both immediate and persistent effects. Significant induction of Cyp1a gene and protein expression was detected after a single 24 h exposure to as little as 1 nM benzo(a)pyrene, and after a 24 h recovery period, Cyp1a expression declined in a dose-dependent manner. However, cell death continued to increase during the recovery period and alterations in microtissue architecture occurred at higher concentrations. To evaluate a pulsed or repeated exposure scenario, microtissues were exposed to benzo(a)pyrene, allowed to recover, then exposed a second time for 24 h. Following pre-exposure to benzo(a)pyrene, cyp1a expression remained equally inducible and the pattern and level of Cyp1a protein response to a second exposure were comparable. However, pre-exposure to 1 μM or 5 μM of benzo(a)pyrene resulted in increased cell death, greater disruption of microtissue architecture, and alterations in cell morphology. Together, this study demonstrates the capabilities of this PLHC-1 microtissue model for sensitive assessment of liver toxicants over time and following single and repeated exposures.

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The role of the efflux carriers Abcg2 and Abcc2 for the hepatobiliary elimination of benzo[a]pyrene and its metabolites in mice

Cited by 19 publications

References 38 publications

Multidrug Resistance Proteins (MRPs) and Cancer Therapy

Multidrug Resistance Proteins (MRPs) and Cancer Therapy

Modulatory Effects of Silymarin on Benzo[a]pyrene-Induced Hepatotoxicity

A 3D fish liver model for aquatic toxicology: Morphological changes and Cyp1a induction in PLHC-1 microtissues after repeated benzo(a)pyrene exposures

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