Probenecid, an inhibitor of transmembrane organic anion transporters, alters tissue distribution of DNA adducts in 1-hydroxymethylpyrene-treated rats

Monien, Bernhard H.; Müller, Carolin; Bakhiya, Nadiya; Donath, Claudia; Frank, Heinz; Seidel, Albrecht; Glatt, Hansruedi

doi:10.1016/j.tox.2009.05.016

Cited by 23 publications

(27 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Probenecid is a potent and broad inhibitor of anion transporters, including the murine basolateral renal tubular Oat family of anion transporters 19 , and the apical Oat2 and Oat 5 20 21 . Since probenecid inhibits other members of the Oatp family 22 it may also be an inhibitor of Oatp4c1, although this has not been specifically reported to our knowledge.…”

Section: Resultsmentioning

confidence: 99%

“…Anion uptake was assessed by incubating live, cultured kidneys growing in the Sebinger culture system with the fluorescent anion 6-CF, either with or without probenecid (2.5 mM) 19 ( Figure 1A ). After allowing uptake to proceed for one hour, both conditions were treated with a higher concentration of probenecid (10 mM) to block efflux of 6-CF by the Mrp-family of efflux pumps, and thus to trap sufficient fluorophore intracellularly for imaging purposes (adapted from methods by Rosines et al 12 , and Rak-Raszewska et al 11 ).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Transport of organic anions and cations in murine embryonic kidney development and in serially-reaggregated engineered kidneys

Lawrence

Chang

Davies

2015

Sci Rep

View full text Add to dashboard Cite

Recent advances in renal tissue engineering have shown that dissociated, early renogenic tissue from the developing embryo can self-assemble into morphologically accurate kidney-like organs arranged around a central collecting duct tree. In order for such self-assembled kidneys to be useful therapeutically or as models for drug screening, it is necessary to demonstrate that they are functional. One of the main functional characteristics of mature kidneys is transport of organic anions and cations into and out of the proximal tubule. Here, we show that the transport function of embryonic kidneys allowed to develop in culture follows a developmental time-course that is comparable to embryonic kidney development in vivo. We also demonstrate that serially-reaggregated engineered kidneys can transport organic anions and cations through specific uptake and efflux channels. These results support the physiological relevance of kidneys grown in culture, a commonly used model for kidney development and research, and suggest that serially-reaggregated kidneys self-assembled from separated cells have some functional characteristics of intact kidneys.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Transport of organic anions and cations in murine embryonic kidney development and in serially-reaggregated engineered kidneys

Lawrence

Chang

Davies

2015

Sci Rep

View full text Add to dashboard Cite

show abstract

“…In addition, probenecid is known to inhibit organic anion transporters of the Scl22a family (Sweet, 2005). Consequently, probenecid was found to cause a modest reduction in 1-hydroxymethylpyrene-mediated DNA-adduct formation in the kidneys of rats with a concomitant increase in DNA-adduct formation in the lungs (Monien et al, 2009). …”

Section: Discussionmentioning

confidence: 99%

Multidrug resistance protein (MRP) 4 attenuates benzo[a]pyrene-mediated DNA-adduct formation in human bronchoalveolar H358 cells

et al. 2012

View full text Add to dashboard Cite

Multi-drug resistance protein (MRP) 4, an ATP-binding cassette (ABC) transporter, has broad substrate specificity. It facilitates the transport of bile salt conjugates, conjugated steroids, nucleoside analogs, eicosanoids, and cardiovascular drugs. Recent studies in liver carcinoma cells and hepatocytes showed that MRP4 expression is regulated by the aryl hydrocarbon receptor (AhR) and nuclear factor E2-related factor 2 (Nrf2). The AhR has particular importance in the lung and is most commonly associated with the up-regulation of cytochrome P-450 (CYP)-mediated metabolism of benzo[a]pyrene (B[a]P) to reactive intermediates. Treatment of H358, human bronchoalveolar, cells with 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) or (−)-benzo[a]pyrene-7,8-dihydro-7,8-diol (B[a]P-7,8-dihydrodiol), the proximate carcinogen of B[a]P, revealed that MRP4 expression was increased compared to control. This suggested that MRP4 expression might contribute to the paradoxical decrease in (+)-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene-2′-deoxyguanosine ((+)-anti-trans-B[a]PDE-dGuo) DNA-adducts observed in TCDD-treated H358 cells. We have now found that decreased MRP4 expression induced by a short hairpin RNA (shRNA), or chemical inhibition with probenecid, increased (+)-anti-trans-B[a]PDE-dGuo formation in cells treated with (−)-B[a]P-7,8-dihydrodiol, but not the ultimate carcinogen (+)-anti-trans-B[a]PDE. Thus, up-regulation of MRP4 increased cellular efflux of (−)-B[a]P-7,8-dihydrodiol, which attenuated DNA-adduct formation. This is the first report identifying a specific MRP efflux transporter that decreases DNA damage arising from an environmental carcinogen.

show abstract

“…1-HMP-DNA adducts were measured by isotope-dilution ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) as described elsewhere (Monien et al 2008). Briefly, DNA (100 μg) was spiked with isotope-labeled standards (250 fmol [ 15 N 5 ] MPdA and 2.5 pmol [ 15 N 5 , 13 C 10 ]MPdG), digested enzymatically to nucleosides, and subjected to solid-phase extraction for enrichment of the adducts as reported (Monien et al 2008;Monien et al 2009). Sample separation was performed using an Acquity UPLC system with a BEH Phenyl column (1.7 μm, 2.1 × 100 mm) and analyzed using a Quattro Premier XE tandem quadrupole mass spectrometer using an electrospray interface operated in the positive ion mode (all from Waters, Eschborn, Germany).…”

Section: Dna Adduct Analysismentioning

confidence: 99%

Impact of p53 function on the sulfotransferase‐mediated bioactivation of the alkylated polycyclic aromatic hydrocarbon 1‐hydroxymethylpyrene in vitro

Wohak

Monien

Phillips

et al. 2019

Environ and Mol Mutagen

View full text Add to dashboard Cite

The tumor suppressor p53, encoded by TP53, is known as the “guardian of the genome.” Sulfotransferases (SULTs) are involved in the metabolism of alkylated polycyclic aromatic hydrocarbons such as 1‐hydroxymethylpyrene (1‐HMP), which is a known substrate for SULT1A1. To investigate the impact of TP53 on the metabolic activation of 1‐HMP, a panel of isogenic human colorectal HCT116 cells having TP53(+/+), TP53(+/−), or TP53(−/−) were treated with 10 μM 1‐HMP for 24 hr. 1‐HMP‐DNA adduct formation was determined by ultraperformance liquid chromatography‐tandem mass spectrometry analysis, which quantified two nucleoside adducts N2‐(1‐methylpyrenyl)‐2′‐deoxyguanosine and N6‐(1‐methylpyrenyl)‐2′‐deoxyadenosine. 1‐HMP treatment resulted in significantly (~40‐fold) higher DNA adduct levels in TP53(+/+) cells than in the other cell lines. Higher levels of 1‐HMP‐induced DNA adducts in TP53(+/+) cells correlated with higher basal expression of SULT1A1/3 in this cell line, but 1‐HMP treatment showed no effect on the expression of this protein. These results indicate that the cellular TP53 status is linked to the SULT1A1/3‐mediated bioactivation of 1‐HMP, thereby broadening the spectrum of p53's targets. Environ. Mol. Mutagen., 60:752–758, 2019. © 2019 Wiley Periodicals, Inc.

show abstract

Probenecid, an inhibitor of transmembrane organic anion transporters, alters tissue distribution of DNA adducts in 1-hydroxymethylpyrene-treated rats

Cited by 23 publications

References 26 publications

Transport of organic anions and cations in murine embryonic kidney development and in serially-reaggregated engineered kidneys

Transport of organic anions and cations in murine embryonic kidney development and in serially-reaggregated engineered kidneys

Multidrug resistance protein (MRP) 4 attenuates benzo[a]pyrene-mediated DNA-adduct formation in human bronchoalveolar H358 cells

Impact of p53 function on the sulfotransferase‐mediated bioactivation of the alkylated polycyclic aromatic hydrocarbon 1‐hydroxymethylpyrene in vitro

Contact Info

Product

Resources

About