Effects of Black Raspberry Extract and Berry Compounds on Repair of

Oct 25, 2017 - Department of Environmental Medicine, New York University School of Medicine, New York, New York 10019, United States. § ... Previousl...
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Effects of Black Raspberry Extract and Berry Compounds on Repair of DNA Damage and Mutagenesis Induced by Chemical and Physical Agents in Human Oral Leukoplakia and Rat Oral Fibroblasts Joseph B. Guttenplan,*,†,∥ Kun-Ming Chen,§ Yuan-Wan Sun,§ Braulio Lajara,† Nora A. E. Shalaby,† Wieslawa Kosinska,† Gabrielle Benitez,§ Krishne Gowda,‡ Shantu Amin,‡ Gary Stoner,⊥ and Karam El-Bayoumy*,§ †

Department of Basic Science, New York University College of Dentistry, New York, New York 10010, United States Department of Environmental Medicine, New York University School of Medicine, New York, New York 10019, United States § Department of Biochemistry and Molecular Biology and ‡Department of Pharmacology, College of Medicine, Pennsylvania State University, Hershey, Pennsylvania 17033, United States ⊥ Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States ∥

S Supporting Information *

ABSTRACT: Black raspberries (BRB) have been shown to inhibit carcinogenesis in a number of systems, with most studies focusing on progression. Previously we reported that an anthocyanin-enriched black raspberry extract (BE) enhanced repair of dibenzo-[a,l]-pyrene dihydrodiol (DBP-diol)-induced DNA adducts and inhibited DBP-diol and DBP-diolepoxide (DBPDE)induced mutagenesis in a lacI rat oral fibroblast cell line, suggesting a role for BRB in the inhibition of initiation of carcinogenesis. Here we extend this work to protection by BE against DNA adduct formation induced by dibenzo-[a,l]-pyrene (DBP) in a human oral leukoplakia cell line (MSK) and to a second carcinogen, UV light. Treatment of MSK cells with DBP and DBPDE led to a dose-dependent increase in DBP-DNA adducts. Treatment of MSK cells with BE after addition of DBP reduced levels of adducts relative to cells treated with DBP alone, and treatment of rat oral fibroblasts with BE after addition of DBPDE inhibited mutagenesis. These observations showed that BE affected repair of DNA adducts and not metabolism of DBP. As a proof of principle we also tested aglycones of two anthocyanins commonly found in berries, delphinidin chloride and pelargonidin chloride. Delphinidin chloride reduced DBP-DNA adduct levels in MSK cells, while PGA did not. These results suggested that certain anthocyanins can enhance repair of bulky DNA adducts. As DBP and its metabolites induced formation of bulky DNA adducts, we investigated the effects of BE on genotoxic effects of a second carcinogen that induces bulky DNA damage, UV light. UV irradiation produced a dose-dependent increase in cyclobutanepyrimidine dimer levels in MSK cells, and post-UV treatment with BE resulted in lower cyclobutanepyrimidine dimer levels. Post-UV treatment of the rat lacI cells with BE reduced UV-induced mutagenesis. Taken together, the results demonstrate that BE extract reduces bulky DNA damage and mutagenesis and support a role for BRB in the inhibition of initiation of carcinogenesis.

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by carcinogens.6 In that study, using lacI rat oral epithelial cells, removal of DNA damage caused by DBP-diol, a primary metabolite of the tobacco-smoke carcinogen, dibenzo-[a,l]-pyrene (DBP) was enhanced when cells were treated with BE before and after carcinogen exposure.6 This latter result and perhaps the former indicated that BE enhanced removal of the DBP-DNA

INTRODUCTION

A number of in vivo and in vitro studies report that black raspberries (BRB) and their extracts (BE) can inhibit several steps in the cancer pathway.1−5 Most previous studies reported that BRB inhibited the later steps of carcinogenesis or did not differentiate between early steps (initiation) and later steps (promotion, progression, metastasis). However, recently we reported that an anthocyanin-enriched BE modulated processes involved in initiation − DNA damage and mutagenesis induced © 2017 American Chemical Society

Received: August 29, 2017 Published: October 25, 2017 2159

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adducts. DBP is metabolized via its metabolite, DBP-diol, to its ultimate carcinogenic metabolites, which are stereoisomers of 11,12-dihydroxy-13,14-epoxy-11,12,13,14-tetrahydrodibenzo[a,l]-pyrene (DBPDE) (Figure 1). DBPDE reacts with DNA to

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EXPERIMENTAL METHODS

Chemicals. DBP was prepared as described in ref 6, and (±)-antiDBPDE was prepared according to another published method by our group.18 Pelargonidin chloride and delphinidin chloride were obtained from Sigma-Aldridge. BE was prepared as described and provided by Dr. Stoner.19 The solvent used to obtain the BE from BRB powder was ethanol/H2O (80:20). Using high-performance liquid chromatography, the extract was shown to be composed of approximately 70% anthocyanins resulting in a concentration of 104 nmol/mg20 and resulting in an anthocyanin concentration in the cell media of about 7.5− 15 μM. The remaining compounds in the BE have not been identified. Cell Lines and Culture Conditions for DNA Adduct and Mutagenesis Assays. The OFB cell line was derived from a lacI (BigBlue) Fisher 344 rat and was kindly provided by David Josephy (University of Guelph, Guelph, Canada). The preparation, characterization, and maintenance of this line have been described previously.21 Cells were grown in DMEM/F12 medium (Corning Cellgro) containing 5% fetal calf serum (Hyclone), glutamine (0.29 mg/mL), and G418-sulfate and penicillin-streptomycin (all from Mediatech) at 0.22 mg/mL. Cells were passaged weekly. MSK-Leuk1 cells were established from a premalignant leukoplakic lesion adjacent to a squamous cell carcinoma of the tongue.12,22 The cells were obtained from Dr. Peter Sacks, who is an emeritus faculty member in the same department as J.B.G. The cells were authenticated by Genetica DNA Laboratories (Burlington, NC) using short tandem repeat DNA profiling on December 8, 2015. Sequencing studies indicated that a GC > AT transition in exon 8 in one allele of p53, resulting in a glu to lys mutation in codon 286, was present in the MSK-Leuk1 cells.22 This cell line was routinely maintained in Keratinocyte Growth Medium (Lonza Bioresearch) grown to 70% confluence and trypsinized with 0.125% trypsin-2 mmol/L EDTA solution before passage. For DBP-DNA adduct assays the MSK cell line was employed. Cells were grown to about 50% confluence on 10 cm diameter cell culture dishes (Corning) and treated with DBP or DBPDE at the concentrations given in Figures 2 and 3. One day later, some of the plates were treated with BE at the concentrations given in the figures and harvested 1 day later. Each measurement was performed in triplicate. For cyclobutanepyrimidine dimer assays, cells were seeded at 3 × 104 cells/well, treated 24 h later, and analyzed for cyclobutanepyrimidine dimer adducts 16 h after that. For all mutagenesis assays the lacI rat oral fibroblast line was used. Cells were grown in 1:1 DMEM/F12 (Corning Cellgro) containing 5% fetal calf serum (Hyclone) to about 20% confluence. At this point,

Figure 1. Structures of DBP, DBP-diol, and two isomers of antiDBPDE.

produce adducts; mainly at adenines7 leading to mutations and cancer in the oral cavity and other organs.8−11 The parent compound, DBP, was ineffective at producing DNA adducts in these cells.6 Here we investigated the effects of BE on DNA adduct formation by DBP and DBPDE in the human oral epithelial cell line, MSK leuk1.12,13 In addition, we investigated the effects of post-mutagen treatment with BE on mutagenesis in lacI rat oral fibroblasts. As polycyclic aromatic hydrocarbons (PAHs) such as DBP lead to helix-distorting or “bulky” DNA adducts,14,15 we studied a second type of carcinogen (UV light) that produces bulky DNA damage. Also, in a preliminary experiment meant to provide clues to the identities of the active components of BE, we investigated the effects of two of the most common anthocyanidins in berries and other fruits (pelargonidin chloride and delphinidin chloride), aglycones of the corresponding anthocyanidins16,17 on DNA damage removal.

Figure 2. Dose response for DNA adducts in MSK cells. (A) Dependence of DNA adduct level on concentration of DBP. (B) Dependence of DNA adduct level on concentration of DBPDE. (C) A representative HPLC-MS/MS chromatogram of DBP-induced dA adducts. (D) A representative HPLC-MS/MS chromatogram of DBPDE-induced dA adducts. (E) A representative HPLC-MS/MS chromatogram of DNA from control cells. Values in (A) represent the mean and SEM from DNA extracted from cells on triplicate plates and in (B) represent DNA adducts from single plates, which were used to establish a dose range. 2160

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Figure 3. Effect of (A) BE, (B) delphinidin Cl (DLP), pelargonidin Cl (PGA) and BE on removal of DBP-dA adducts at two concentrations of DBP in MSK cells. Cells were treated with DBP. One day later BE, delphinidin chloride, or pelargonidin chloride was added. One day later (48 h after addition of DBP) adducts were analyzed. *, P ≤ 0.05 in a one-tailed t test; **, P ≤ 0.01 in a one-tailed t test vs corresponding group with no additive Structures of DLP and PGA. the medium was replaced with 10 mL of DMEM/F12 medium without serum, and cells were treated with DBPDE with or without BE at time intervals described in Figure 4. For UV-induced mutagenesis, BE

levels without inhibitor varied from experiment to experiment, but were internally consistent. That is, each panel in the figures represents an experiment performed on a different day, and controls and experimental samples can be compared within results from each day, but not across different days. Each condition was assayed from triplicate plates except where there are no error bars in the figure; these represent single plates and were used to establish a dose range. Results in the figures represent the major adduct, (−)-anti-trans-DBP-dA. Mutagenesis Assay. After treatment of the lacI cells with mutagen ± BE, DNA was extracted using a Recoverase kit (Agilent Technologies) as per manufacturer’s instructions, which involved isolation of nuclei, cell lysis, digestion with protease K, RNase, and dialysis on a membrane. Phage packaging was carried out using a phage packaging mix prepared from bacterial strains E. coli NM759 and BHB2688, generously supplied by Dr. Peter Glazer (Yale, University School of Medicine, New Haven, CT) according to published methods.25 The cII mutagenesis assay was then employed.26 Briefly, the isolated DNA was treated with the phage packaging extract, which contains all the components necessary for the in vitro assembly of a lambda phage containing in the phage head a vector that includes the bacterial lacI locus and the cII gene, the target for the mutagenesis assay. It also obviates the potential for ex vivo mutations that could complicate results. This assay detects mutations at the cII locus and possibly the regulator cI locus.26−30 The cII protein is a positive regulator of gene transcription that controls the decision between lytic or lysogenic development pathways in phage-infected E. coli cells. In appropriate E. coli (E. coli 1250) host cells under specified conditions (25 °C), only mutants give rise to phage plaques, whereas at 37 °C all infected cells give rise to plaques, providing a phage titer.26−30 The mutant fraction (MF) is the ratio of mutant to nonmutant plaques and is the measure of mutagenesis. Plates for each condition were done in triplicate. Experiments using DBPDE with and without BE were performed on different days, and the absolute values for mutagenesis with and without inhibitor varied from experiment to experiment, but were internally consistent. Analysis of 11,12,13,14-Tetrahydroxy-11,12,13,14-tetrahydrodibenzo-[a,l]-pyrene (DBP-Tetrol). DBPDE spontaneously hydrolyzed into two isomers of DBP-tetrol. These were analyzed by HPLC. Elution was performed using a Shimadzu LC20AD system and a Waters C18 Symmetry column (2.1 × 150 mm, 3.5 μm particle size) at a flow rate of 0.2 mL/min in a pH 4.0, 4 mM sodium phosphate buffer containing 45% acetonitrile. A fluorescence detector (Shimadzu, RF10Axl) was set at 344 nm excitation and 400 emission. UV Irradiation. Cells were irradiated, cap off, a single plate at a time in a Stratalinker 1800 Gel Cross-linker for the indicated exposure. The light intensity was related to time of exposure by the relationship, 47 s exposure = 100 mjoules/cm2. For some initial experiments, cells were irradiated a single G30T8 germicidal lamp 30 in. above the plate in laminar flow hood. Assay for Cyclobutanepyrimidine Dimers. Cyclobutanepyrimidine dimers in DNA were assayed in 96 well plates using an OxiSelect Cellular UV-Induced DNA Damage ELISA Kit purchased from Cell Biolabs, following the manufacturer’s instructions. Antibody treated unirradiated controls were used to establish a background.

Figure 4. Effect of time of addition of 160 μg/mL BE on mutagenesis induced by DBPDE in lacI rat oral fibroblasts. BE was added either 1 h before or 1 h after DBPDE. Experiments were conducted at two different concentrations of DBPDE on different days and are expressed as relative levels of mutagenesis. The mutant factions for the DBPDEalone treated cells were 50.1 and 53.8 mutants/105 pfu at 50 and 100 nM DBPDE, respectively. or vehicle was added immediately after treatment. One h after the last treatment, the serum concentration was brought to 5%. As mutagenesis requires replication, the cells were incubated at 37 °C for 72 h before harvesting. All treatments were carried out in triplicate. Analysis of DNA DBP-DNA Adducts. As reported by us, DBPDE-dA is the major DNA adduct detected in mice treated with DBP.23 The method used for analysis of the DBPDE-dA adducts by LC-MS/MS is identical to our previously published procedure.7,23,24 In brief, DNA was isolated from cells using the Qiagen DNA easy kit as described by the manufacturer. The concentration of DNA was determined using a NanoDrop ND-1000 spectrophotometer (NanoDrop Technologies, Wilmington, DE). Prior to enzymatic digestion, 150 pg of each [15N5]-(−)-anti-trans- and [15N5]-(−)-anti-cis-DBPDEdA adducts were added to ∼100 μg DNA. DNA was hydrolyzed in the presence of 10 mM MgCl2 (10 μL/mg DNA) and DNase I (0.2 mg/mg DNA) at 37 °C for 1.5 h. Subsequently, nuclease P1 (20 μg/mg DNA) snake venom phosphodiesterase (0.08 unit/mg DNA) and alkaline phosphatase (2 units/mg DNA) were used. An aliquot of the DNA hydrolysate was subjected to dA base analysis by HPLC. The remaining supernatant was partially purified by solid-phase extraction using an Oasis HLB column (1 cm3, 30 mg, Waters Ltd.). Then, the analysis was carried out on an API 3200 LC/MS/MS triple quadrupole mass spectrometer interfaced with an Agilent 1200 series HPLC using an Agilent extend-C18 5 μm 4.6 × 150 mm column. Adducts were monitored in multiple reaction monitoring (MRM) mode. The MS/MS transitions of m/z 604 → m/z 335, and m/z 609 → m/z 335 were monitored for targeted adducts and internal standards, respectively. Experiments using DBP and DBPDE with and without BE were performed on different days, and the absolute values of DNA adduct 2161

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Chemical Research in Toxicology Irradiation times and concentrations of BE are described in Figure 5. Each measurement was carried out in triplicate.

Effects of BE on DNA Adduct Levels and Mutagenesis Induced by UV Irradiation. Cyclobutanepyrimidine Dimers. To assess whether BE enhanced repair of UV-induced damage to DNA, an ELISA assay, which measured relative cyclobutanepyrimidine dimer levels, was employed. Cells were irradiated in a Stratalinker UV Cross-linker in 96 well plates for the times indicated in the figures, and immediately after irradiation, BE was added. Sixteen h later cyclobutanepyrimidine dimers in denatured MSK cells were measured. BE significantly reduced the level of cyclobutanepyrimidine dimers by about 40% at two irradiation times (Figure 5). Mutagenesis. As treatment with BE after UV irradiation led to reduced DNA damage, we anticipated it would also reduce UV-induced mutagenesis. For this experiment lacI rat oral fibroblasts were irradiated with UV light, and BE was added after irradiation. As shown in Figure 6, BE added subsequent to

Figure 5. Effect of 160 μg/mL BE on UV-induced cyclobutanepyrimidine dimer levels after 4 and 8 min of exposure in 96 well plates. The absorbance (ordinate) represents the signal for cyclobutanepyrimidine dimers in the ELISA assay. Hazardous Materials. Caution: DB-[a,l]-P and DB-[a,l]-PDE are mutagenic and carcinogenic. They should be handled with extreme care, following NCI safety guidelines: (http://pubs.acs.org/doi/abs/10.1021/ ed052pA419).

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RESULTS DNA Damage and Mutagenesis Induced by DBP and DBPDE. DNA Damage. DBP and DBPDE produced DNA adducts in MSK cells (Figure 2A,B). With DBP, adduct levels plateaued around 1 μM, probably reflecting saturation of the enzymes metabolizing DBP (Figure 2A). DBPDE does not require metabolic activation and exhibited a near linear dose−response (Figure 2B). Representative HPLC-MS/MS tracings are included in Figure 2C−E. Also, a figure showing the ion transitions resulting from mass spectral fragmentation of the DBPDE-dA adduct is included in the Supporting Information. We then tested whether BE could inhibit DNA adduct formation in MSK cells when added 24 h after treatment with DBP. At this time point, formation of DBPDE from DBP leveled off, and no additional DBPDE was formed, as assayed by the plateauing of the DBPDE hydrolysis product, 11,12,13, 14-tetrahydroxy-11,12,13,14-tetrahydrodibenzo-[a,l]-pyrene in the medium (Supporting Information, Figure 2). We tested the effects of BE on DNA adduct formation at two concentrations of DBP and two concentrations of BE, and both showed a dose-dependent inhibition of DNA adduct formation (Figure 3A,B). As a first step in characterizing the agents responsible for the enhanced DNA repair induced by the BE, we tested the aglycones of two anthocyanins present in BE. One of these, delphinidin chloride, was effective at inhibiting repair of the major DBP-induced adenine adduct, and the other, pelargonidin (PGA) was not (Figure 3B). Mutagenesis. Previously we reported that an overnight pretreatment of lacI rat oral fibroblasts with BE before addition of DBPDE led to substantial reduction of mutagenesis.6 In the current study we modified the protocol so that there was either a short pretreatment period with BE before addition of DBPDE at two different concentrations or a treatment with BE shortly after addition of DBPDE. When 160 μg/mL BE was added to MSK cells 1 h before DBPDE, it reduced mutagenesis to about 10% of the DBPDE-alone treated cells. When added 1 h after DBPDE, BE reduced mutagenesis to about 65% of the DBPDEalone cells (Figure 4)

Figure 6. Effect of 160 μg/mL BE on mutagenesis induced in lacI oral fibroblasts at different irradiation times. *, P ≤ 0.05 in a one-tailed t test vs the group with no BE.

UV irradiation significantly reduced mutagenesis at several different irradiation times.

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DISCUSSION DNA Damage and Repair. Previously we reported that DBP and DBP-diol are metabolized to DBP intermediates that bind to DNA and lead to mutagenesis in mouse oral tissue and in a lacI rat oral fibroblast cell line resp.7,9,24,31 The ultimate genotoxic metabolite, DBPDE, produced DNA adducts and was mutagenic without metabolic activation.31 The rat oral cells were employed in that study because they contain a mutagenesis reporter gene,21 which was necessary for studies in mutagenesis assays. It would have been desirable to employ the parent compound, DBP, as it is present in tobacco smoke32 and is also a model for other polycyclic aromatic hydrocarbon carcinogens, but it was not metabolized by these cells to a DNA binding or mutagenic products.6 In the present study, we observed that the human oral epithelial cell line, MSK, was capable of metabolizing DBP to DNA binding products (Figure 2A). We also found that DBPDE bound to DNA in this cell line (Figure 2B) leading to the same DNA adducts, indicating that the metabolism of DBP to DNA binding products proceeded through DBPDE. We also previously demonstrated that DBPDE adduct levels declined when going from 24 to 48 h after treatment with DBP diol, and the decline was significantly greater in cells treated with BE, even when treated with BE 24 h after DBP-diol.6 This indicated that at least part of the inhibitory activity of BE resulted from BE enhancement of DNA repair.6 In the current study we tested whether treatment with BE reduced DNA 2162

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mic repair, which acts on helix-distorting lesions or transcriptioncoupled repair which is triggered by transcription-blocking lesions.35 The effects of BE could include inducing DNA damage recognition or signaling proteins, enhancing excision and resynthesis, and slowing progression through the cell cycle, allowing more time for DNA repair. Future studies will investigate which proteins are modulated by BE and which components of BE are responsible for its protective effects on NER. In addition, we intend to examine the effects of BRB on other DNA repair systems such as base-excision repair and double-strand break repair.

damage resulting from DBP in human oral cells when administered 24 h post-carcinogen. By 24 h after addition of DBP, metabolism to DBPDE was complete (Supporting Information, Figure 2). We also determined that the BE did not enhance the rate cell proliferation (which would dilute the adduct levels with new DNA), as monitored in an MTT assay (results not shown). Taken together then, the results indicate that the reduction in adduct levels resulted from enhanced removal in the BE treated cells. DNA adducts resulting from polycyclic aromatic hydrocarbons are helix-distorting and are repaired by the NER system.14 We then reasoned that repair of other types of bulky lesions might be enhanced by BE. Hence we investigated the effect of BE on repair of a UV-light induced bulky lesion, the cyclobutanepyrimidine dimer. Similar to results with DBP, BE, added post UV-treatment, resulted in reduced levels of adducts relative to UV-alone treated cells (Figure 5). Mutagenesis. Previously we showed that BE added 24 h before DBPDE inhibited mutagenesis.6 Using that protocol, it was not certain whether BE was acting to detoxify DBPDE or exert a post-damage effect. Based on the ability of BE to enhance repair of DBP-DNA adducts, we tested BE against DBPDEinduced mutagenesis by treating with BE shortly before or after treatment with DBPDE. We observed that BE, added just 1 h before or even 1 h after DBPDE, reduced DBPDE-induced mutagenesis (Figure 4). When added after DBPDE, the reduction in mutagenesis was less striking, but still significant. It appears that the antimutagenic processes occur relatively rapidly, allowing DNA damage to be removed before replication across DNA damage leads to mutations. Similar to the results in the DNA damage assay, these results support a mechanism of inhibition involving enhanced repair of damage by BE. As with DBP, postUV treatment with BE reduced mutagenesis induced by UV light (Figure 6). We did not test the effect of BE added before UV irradiation because components in the BE might photochemically decompose or lead to free radicals or singlet oxygen. In a proof-of-principle experiment, the aglycones of two of the major berry anthocyanins were tested for their abilities to inhibit DNA damage (Figure 3B). One of them, pelargonidin chloride, was ineffective, and the other, delphinidin chloride, was effective. The structures of the two molecules are very similar (Figure 3), but delphinidin chloride contains two more hydroxyls than pelargonidin chloride, indicating that specific structural features are necessary for enhancement of DNA repair. The concentration of delphinidin chloride in our study is much higher than that of any individual anthocyanins monitored in humans after consumption or exposure to BRB.33,34 However, there are numerous potential delphinidin chloride sugar conjugates, and there are likely a number of anthocyanins with similar structural features as delphinidin chloride in BRB. The mixture of these components would then provide a higher concentration of DNA-repair enhancing compounds than that of delphinidin chloride alone. The total concentrations of anthocyanins in the BE-containing media in the present study are in the range of delphidin concentrations used here (see Experimental Methods). In conclusion, results from DNA damage assays on cells treated with DBP, or UV light, followed by BE, demonstrated that BE enhanced the removal of bulky DNA adducts. Consistent with these observations were results in the mutagenesis assays where cells treated with DBPDE or UV light after carcinogen exposure were protected by BE. Bulky DNA adducts are repaired by the NER system.35 This system is comprised of multiple proteins, and the initial steps may involve global geno-

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.chemrestox.7b00242. The ion transitions resulting from mass spectral fragmentation of the DBPDE-dA adduct. Time course of metabolism of DBP to DBP-tetrols by human oral cells (MSK leuk1) (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. Tel: 212-998-9604. *E-mail: [email protected]. Tel: 717-531-1005. ORCID

Joseph B. Guttenplan: 0000-0002-8873-9349 Karam El-Bayoumy: 0000-0002-4198-0696 Funding

Supported by NIH grant no. CA 173465. Notes

The authors declare no competing financial interest.

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ABBREVIATIONS BRB, black raspberry; BE, black raspberry extract; DBP, dibenzo-(a,l)-pyrene; DBP-diol, 11,12-dihydroxy-11,12,-dihydrodibenzo-[a,l]-pyrene; DBPDE, 11,12-dihydroxy-13,14epoxy-11,12,13,14-tetrahydrodibenzo-[a,l]-pyrene; DBP-tetrol, 11,12,13,14-tetrahydroxy-11,12,13,14-tetrahydrodibenzo-[a,l]pyrene; MSK leuk1, human oral epithelial cell line

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REFERENCES

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DOI: 10.1021/acs.chemrestox.7b00242 Chem. Res. Toxicol. 2017, 30, 2159−2164

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DOI: 10.1021/acs.chemrestox.7b00242 Chem. Res. Toxicol. 2017, 30, 2159−2164