In Vivo Inflammation Does Not Impair ABCA1-Mediated Cholesterol Efflux Capacity of HDL

HDL provides atheroprotection by facilitating cholesterol efflex from lipid-laden macrophages in the vessel wall. In vitro studies have suggested impaired efflux capacity of HDL following inflammatory changes. We assessed the impact of acute severe sepsis and mild chronic inflammatory disease on the efflux capacity of HDL. We hypothesize that a more severe inflammatory state leads to stronger impaired cholesterol efflux capacity. Using lipid-laden THP1 cells and fibroblasts we were able to show that efflux capacity of HDL from both patients with severe sepsis or with Crohn's disease (active or in remission), either isolated using density gradient ultracentrifugation or using apoB precipitation, was not impaired. Yet plasma levels of HDL cholesterol and apoA-I were markedly lower in patients with sepsis. Based on the current observations we conclude that inflammatory disease does not interfere with the capacity of HDL to mediate cholesterol efflux. Our findings do not lend support to the biological relevance of HDL function changes in vitro.

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Abstract 319: Dalcetrapib-Mediated Modulation of Cholesteryl Ester Transfer Protein Activity Increases HDL-Cholesterol, Apolipoprotein A-I Levels and Cholesterol Efflux Capacity in Chow-Fed Rabbits

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.32.suppl_1.a319 ◽

2012 ◽

Vol 32 (suppl_1) ◽

Author(s):

Mathieu R Brodeur ◽

David Rhainds ◽

Daniel Charpentier ◽

Téodora Mihalache-Avram ◽

Cyrille Maugeais ◽

...

Keyword(s):

Cholesteryl Ester ◽

Cholesteryl Ester Transfer Protein ◽

Cholesterol Efflux ◽

Hdl Cholesterol ◽

Lipid Transfer ◽

Protein Activity ◽

Cholesterol Efflux Capacity ◽

Transfer Protein

Introduction: A potential approach to reduce CV risk is to increase HDL-C levels. This could be achieved by reducing cholesteryl ester transfer protein (CETP) activity. Dalcetrapib, which modulates CETP activity by changing its conformation and raises HDL-C without inhibiting CETP-induced pre-β-HDL formation in humans, was shown to decrease progression of atherosclerosis in rabbits. Hypothesis: Investigate the modifications of HDL particle size distribution and cholesterol efflux capacity of serum produced by dalcetrapib in normocholesterolemic rabbits. Methods: New Zealand white rabbits were treated with dalcetrapib (300 mg/kg as food admix) or placebo for 14 days. We evaluated CETP conformation and mass by ELISAs (including antibodies sensitive to conformational change), CETP activity by fluorescent lipid transfer, lipid profile and apoA-I distribution in HDL subclasses by 2D-non denaturing gradient gels (2D-NDGGE). Cholesterol efflux capacity of rabbit sera was determined after loading cells with 3 H-free cholesterol, using HepG2 hepatocytes to measure SR-BI-dependent efflux and by inducing ABCA1 or ABCG1 expression in BHK cells. Results: Dalcetrapib modified the conformation of rabbit CETP in vitro and in vivo and, after 14 days, this was associated with increased CETP mass (+50%, p<0.001) and reduced CETP activity (-86%, p<0.001). Total cholesterol was increased with dalcetrapib (+178%, p<0.001), due to a higher HDL-C level. In contrast, dalcetrapib reduced LDL-C and triglycerides by 41% (p<0.01) and 48% (p<0.001). Serum analysis by 2D-NDGGE showed that total rabbit apoA-I was increased 1.7- fold in animals treated with dalcetrapib. This was associated with an increase in large HDL but also in small α-migrating HDL with pre-β-HDL size. Cholesterol efflux assays showed that ABCA1-, ABCG1- and SR-BI-dependent efflux were all increased in dalcetrapib-treated rabbits (+24%, p=0.038; +21%, p=0.021; +44%, p<0.001). Conclusion: Modulation of CETP activity and conformation by dalcetrapib increases HDL-C and apoA-I levels and affects apoA-I distribution in HDL subclasses. These changes are associated with increased cholesterol efflux capacity, suggesting that HDL functionality is preserved in dalcetrapib-treated chow-fed rabbits.

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Abstract 576: Salicylamine, A γ-ketoaldehyde Scavenger, Improves HDL Function and Reduces Atherosclerosis in Apoe Deficient Mice

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.37.suppl_1.576 ◽

2017 ◽

Vol 37 (suppl_1) ◽

Author(s):

Jiansheng Huang ◽

Patricia Yancey ◽

Lei Ding ◽

Youmin Zhang ◽

John Oates ◽

...

Keyword(s):

Western Blot ◽

Cholesterol Efflux ◽

Adduct Formation ◽

Molar Ratio ◽

Atherosclerotic Cardiovascular Disease ◽

Dependent Manner ◽

Cholesterol Accumulation ◽

Cholesterol Efflux Capacity ◽

Hdl Function ◽

The Impact

Background: Lipid peroxidation products impair the cholesterol efflux capacity of high-density lipoprotein (HDL) and promote the development of atherosclerosis. The impact of inhibition of malondialdehyde (MDA)-HDL adduct formation by scavengers on HDL function and whether small molecule aldehyde scavengers protect against the development of atherosclerosis was examined. Methods and Results: Western blot analysis of ApoAI revealed that the amount of ApoAI crosslinking increased with MDA concentration. In the presence of LPS, MDA-HDL (HDL modified by 1mM MDA) versus control HDL stimulated 2- and 1.8-fold more expression of TNF-α and IL-1β in Apoe-/- macrophages demonstrating that MDA-HDL has reduced anti-inflammatory function. HDL-mediated macrophage cholesterol efflux was decreased by ~ 42%, 55%, 70%, and 80%, respectively, for HDL modified with 0.125 mM, 0.25 mM, 0.5 mM, and 1mM MDA, demonstrating that MDA modification of HDL affects its cholesterol efflux capacity in a dose dependent manner. Analysis by Western blot demonstrated that 5mM of salicylamine (SAM) and 5mM of pentylpyridoxamine (PPM), γ-ketoaldehyde scavengers, attenuated MDA mediated crosslinking of apoA-I in HDL (molar ratio of MDA and HDL is 1:5) by 60% and 80 % (P<0.05), respectively. Both SAM and PPM maintained the cholesterol efflux capacity of MDA treated HDL in Apoe-/- macrophages. In addition, pretreatment of LDL with SAM prevented MDA-ApoB adduct formation, and compared to incubation with LDL containing MDA-ApoB adducts, SAM treatment resulted in 57% less cholesterol accumulation in J774 macrophages. Importantly, administration of the ketoaldehyde scavenger, SAM, versus the nonreactive analogue, 4-SAM, to Apoe-/- mice consuming a Western diet for 16 weeks reduced the extent of proximal aortic atherosclerosis by 28% (P<0.05). Conclusions: Treatment with salicylamine, a γ-ketoaldehyde scavenger: 1) inhibits MDA-ApoA1 adduct formation thereby preserving HDL cholesterol efflux capacity; 2) prevents MDA-apoB100 formation resulting in less macrophage cholesterol accumulation; 3) reduces atherosclerosis in Apoe -/- mice. These results support the therapeutic potential of salicylamine in the treatment of atherosclerotic cardiovascular disease.

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Scavenging dicarbonyls with 5’-O-pentyl-pyridoxamine improves insulin sensitivity and reduces atherosclerosis through modulating inflammatory Ly6Chi monocytosis and macrophage polarization

10.1101/529339 ◽

2019 ◽

Author(s):

Jiansheng Huang ◽

Patricia G. Yancey ◽

Linda S. May-Zhang ◽

Huan Tao ◽

Youmin Zhang ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Cholesterol Efflux ◽

Macrophage Polarization ◽

Atherosclerotic Cardiovascular Disease ◽

Aortic Lesion ◽

Cholesterol Efflux Capacity ◽

Atherosclerotic Lesions ◽

Hdl Function

BackgroundLipid peroxidation products impair HDL function and contribute to the development of atherosclerosis. Ours and other studies have shown that reactive dicarbonyls such as Isolevuglandins (IsoLG) and malondialdehyde (MDA), crosslink apoAI and impair the ability of HDL to promote cholesterol efflux. We examined whether scavenging of reactive dicarbonyls protects against the development of insulin resistance and atherosclerosis.Methods and ResultsHere, we found that 5’-O-pentyl-pyridoxamine (PPM), a potent scavenger of reactive dicarbonyls, abolished MDA-mediated crosslinking of apoAI in HDL by 80 % (P<0.05). In addition, PPM prevented the reduction in cholesterol efflux capacity of MDA treated HDL and preserved the cholesterol efflux capacity of MPO-modified HDL in Apoe−/− macrophages. Furthermore, PPM significantly improved the cholesterol efflux capacity and PON1 activity of HDL in Ldlr−/− mice (P<0.05), indicating that PPM protects HDL from modifications by reactive dicarbonyls and maintains HDL function in vivo. Importantly, PPM improved hyperglycemia and insulin sensitivity in male Ldlr−/− mice. Administration of 1 mg/mL of PPM, versus 1 mg/mL of the nonreactive analogue PPO, to Ldlr−/− mice consuming a western diet (WD) for 16 weeks reduced the extent of proximal aortic atherosclerosis by 48% and by 46% (P<0.05) in female and male Ldlr−/− mice. PPM also reduced the extent of en face aortic lesion by 52% in male Ldlr−/− mice. In addition, PPM reduced pro-inflammatory enzyme MPO expression by 57.5% and the number of TUNEL positive cells by 52% (P<0.01) in atherosclerotic lesions of Ldlr−/− mice. Immunohistochemistry studies revealed that PPM reduced the lesion macrophage content by 55% (P<0.05). Importantly, PPM increased M2 marker Arg1+ in macrophages of lesions and reduced the number of blood pro-inflammatory Ly6Chi monocytes and the ratio between Ly6Chi and Ly6Clow, but not the numbers of Ly6Clow, neutrophils in Ldlr−/− mice. Similarly, treatment of Apoe−/− mice on a WD for 16 weeks with PPM significantly reduced the extent of atherosclerotic lesions and also enhanced plaque stability as evidenced by a 47% increase in fibrous cap thickness and a 64.7% reduction in necrotic core area.ConclusionsReactive dicarbonyl scavenging with PPM in vivo preserves HDL function which improves insulin sensitivity and decreases atherosclerosis development. These results support the therapeutic potential of reactive dicarbonyl scavenging in the treatment of insulin resistance and atherosclerotic cardiovascular disease.

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HDL Cholesterol Efflux Capacity is Impaired in Severe Short-Term Hypothyroidism Despite Increased HDL Cholesterol

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa411 ◽

2020 ◽

Vol 105 (9) ◽

pp. e3355-e3362

Author(s):

Trynke van der Boom ◽

Congzhuo Jia ◽

Joop D Lefrandt ◽

Margery A Connelly ◽

Thera P Links ◽

...

Keyword(s):

Cholesterol Efflux ◽

Particle Concentration ◽

Density Lipoprotein ◽

Hdl Cholesterol ◽

Antioxidative Capacity ◽

Short Term ◽

Cholesterol Efflux Capacity ◽

Hdl Function ◽

Particle Characteristics ◽

The Impact

Abstract Context Severe hypothyroidism has profound effects on lipoprotein metabolism including high-density lipoprotein (HDL) cholesterol elevations but effects on HDL function metrics are unknown. Objective To determine the impact of severe short-term hypothyroidism on HDL particle characteristics, HDL cholesterol efflux capacity (CEC), and HDL antioxidative capacity. Design Observational study with variables measured during severe short-term hypothyroidism (median TSH 81 mU/L) and after 20 weeks of thyroid hormone supplementation (median TSH 0.03 mU/L) (Netherlands Trial Registry ID 7228). Setting University hospital setting in The Netherlands. Patients Seventeen patients who had undergone a total thyroidectomy for differentiated thyroid carcinoma. Main outcome measures HDL particle characteristics (nuclear magnetic resonance spectrometry), CEC (human THP-1-derived macrophage foam cells and apolipoprotein B-depleted plasma), and HDL anti-oxidative capacity (inhibition of low-density lipoprotein oxidation). Results During hypothyroidism plasma total cholesterol, HDL cholesterol and apolipoprotein A-I were increased (P ≤ 0.001). HDL particle concentration was unchanged, but there was a shift in HDL subclasses toward larger HDL particles (P < 0.001). CEC was decreased (P = 0.035), also when corrected for HDL cholesterol (P < 0.001) or HDL particle concentration (P = 0.011). HDL antioxidative capacity did not change. Conclusion During severe short-term hypothyroidism CEC, an important antiatherogenic metric of HDL function, is impaired. HDL cholesterol and larger HDL particles are increased but HDL particle concentration is unchanged. Combined, these findings suggest that HDL quality and quantity are not improved, reflecting dysfunctional HDL in hypothyroidism.

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Reactive Dicarbonyl Scavenging Effectively Reduces MPO-Mediated Oxidation of HDL and Restores PON1 Activity

Nutrients ◽

10.3390/nu12071937 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1937 ◽

Cited By ~ 1

Author(s):

Jiansheng Huang ◽

Patricia G. Yancey ◽

Huan Tao ◽

Mark S. Borja ◽

Loren E. Smith ◽

...

Keyword(s):

Cholesterol Efflux ◽

Adduct Formation ◽

Paraoxonase 1 ◽

High Density Lipoproteins ◽

Pon1 Activity ◽

Cholesterol Efflux Capacity ◽

Hdl Function ◽

Impaired Ability ◽

The Impact ◽

Mediated Oxidation

Atheroprotective functions of high-density lipoproteins (HDL) are related to the activity of HDL-associated enzymes such as paraoxonase 1 (PON1). We examined the impact of inhibition of myeloperoxidase (MPO)-mediated HDL oxidation by PON1 on HDL malondialdehyde (MDA) content and HDL function. In the presence of PON1, crosslinking of apoAI in response to MPO-mediated oxidation of HDL was abolished, and MDA-HDL adduct levels were decreased. PON1 prevented the impaired cholesterol efflux capacity of MPO-oxidized HDL from Apoe−/− macrophages. Direct modification of HDL with MDA increased apoAI crosslinking and reduced the cholesterol efflux capacity. MDA modification of HDL reduced its anti-inflammatory function compared to native HDL. MDA-HDL also had impaired ability to increase PON1 activity. Importantly, HDL from subjects with familial hypercholesterolemia (FH-HDL) versus controls had increased MDA-apoAI adducts, and PON1 activity was also impaired in FH. Consistently, FH-HDL induced a pro-inflammatory response in Apoe−/− macrophages and had an impaired ability to promote cholesterol efflux. Interestingly, reactive dicarbonyl scavengers, including 2-hydroxybenzylamine (2-HOBA) and pentyl-pyridoxamine (PPM), effectively abolished MPO-mediated apoAI crosslinking, MDA adduct formation, and improved cholesterol efflux capacity. Treatment of hypercholesterolemic mice with reactive dicarbonyl scavengers reduced MDA-HDL adduct formation and increased HDL cholesterol efflux capacity, supporting the therapeutic potential of reactive carbonyl scavenging for improving HDL function.

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The impact of Zataria multiflora Boiss extract on in vitro and in vivo Th1/Th2 cytokine (IFN-γ/IL4) balance

Journal of Ethnopharmacology ◽

10.1016/j.jep.2013.10.003 ◽

2013 ◽

Vol 150 (3) ◽

pp. 1024-1031 ◽

Cited By ~ 35

Author(s):

Mohammad Hossein Boskabady ◽

Sakine Shahmohammadi Mehrjardi ◽

Abadorrahim Rezaee ◽

Houshang Rafatpanah ◽

Sediqeh Jalali

Keyword(s):

Zataria Multiflora ◽

Th2 Cytokine ◽

Ifn Γ ◽

The Impact

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The impact of FGF19/FGFR4 signaling inhibition in antitumor activity of multi-kinase inhibitors in hepatocellular carcinoma

Scientific Reports ◽

10.1038/s41598-021-84117-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Hiroaki Kanzaki ◽

Tetsuhiro Chiba ◽

Junjie Ao ◽

Keisuke Koroki ◽

Kengo Kanayama ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Molecular Mechanisms ◽

Kinase Inhibitors ◽

Progression Free Survival ◽

Erk Signaling ◽

Enzyme Linked Immunosorbent Assay ◽

Antitumor Effects ◽

The Impact

AbstractFGF19/FGFR4 autocrine signaling is one of the main targets for multi-kinase inhibitors (MKIs). However, the molecular mechanisms underlying FGF19/FGFR4 signaling in the antitumor effects to MKIs in hepatocellular carcinoma (HCC) remain unclear. In this study, the impact of FGFR4/ERK signaling inhibition on HCC following MKI treatment was analyzed in vitro and in vivo assays. Serum FGF19 in HCC patients treated using MKIs, such as sorafenib (n = 173) and lenvatinib (n = 40), was measured by enzyme-linked immunosorbent assay. Lenvatinib strongly inhibited the phosphorylation of FRS2 and ERK, the downstream signaling molecules of FGFR4, compared with sorafenib and regorafenib. Additional use of a selective FGFR4 inhibitor with sorafenib further suppressed FGFR4/ERK signaling and synergistically inhibited HCC cell growth in culture and xenograft subcutaneous tumors. Although serum FGF19high (n = 68) patients treated using sorafenib exhibited a significantly shorter progression-free survival and overall survival than FGF19low (n = 105) patients, there were no significant differences between FGF19high (n = 21) and FGF19low (n = 19) patients treated using lenvatinib. In conclusion, robust inhibition of FGF19/FGFR4 is of importance for the exertion of antitumor effects of MKIs. Serum FGF19 levels may function as a predictive marker for drug response and survival in HCC patients treated using sorafenib.

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Transcriptional Profiling of Porcine Blastocysts Produced In Vitro in a Chemically Defined Culture Medium

Animals ◽

10.3390/ani11051414 ◽

2021 ◽

Vol 11 (5) ◽

pp. 1414

Author(s):

Josep M. Cambra ◽

Emilio A. Martinez ◽

Heriberto Rodriguez-Martinez ◽

Maria A. Gil ◽

Cristina Cuello

Keyword(s):

Culture Medium ◽

Embryo Quality ◽

Transcriptional Profiling ◽

Defined Medium ◽

Platelet Factor ◽

Defined Media ◽

Defined Culture ◽

The Impact

The development of chemically defined media is a growing trend in in vitro embryo production (IVP). Recently, traditional undefined culture medium with bovine serum albumin (BSA) has been successfully replaced by a chemically defined medium using substances with embryotrophic properties such as platelet factor 4 (PF4). Although the use of this medium sustains IVP, the impact of defined media on the embryonic transcriptome has not been fully elucidated. This study analyzed the transcriptome of porcine IVP blastocysts, cultured in defined (PF4 group) and undefined media (BSA group) by microarrays. In vivo-derived blastocysts (IVV group) were used as a standard of maximum embryo quality. The results showed no differentially expressed genes (DEG) between the PF4 and BSA groups. However, a total of 2780 and 2577 DEGs were detected when comparing the PF4 or the BSA group with the IVV group, respectively. Most of these genes were common in both in vitro groups (2132) and present in some enriched pathways, such as cell cycle, lysosome and/or metabolic pathways. These results show that IVP conditions strongly affect embryo transcriptome and that the defined culture medium with PF4 is a guaranteed replacement for traditional culture with BSA.

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Impact of RARα and miR-138 on retinoblastoma etoposide resistance

Tumor Biology ◽

10.3233/tub-200072 ◽

2021 ◽

Vol 43 (1) ◽

pp. 11-26

Author(s):

Maike Busch ◽

Natalia Miroschnikov ◽

Jaroslaw Thomas Dankert ◽

Marc Wiesehöfer ◽

Klaus Metz ◽

...

Keyword(s):

Cell Viability ◽

Cell Lines ◽

Cancer Progression ◽

Treated Patient ◽

Luciferase Reporter ◽

Luciferase Reporter Gene ◽

Gene Assay ◽

The Impact

BACKGROUND: Retinoblastoma (RB) is the most common childhood eye cancer. Chemotherapeutic drugs such as etoposide used in RB treatment often cause massive side effects and acquired drug resistances. Dysregulated genes and miRNAs have a large impact on cancer progression and development of chemotherapy resistances. OBJECTIVE: This study was designed to investigate the involvement of retinoic acid receptor alpha (RARα) in RB progression and chemoresistance as well as the impact of miR-138, a potential RARα regulating miRNA. METHODS: RARα and miR-138 expression in etoposide resistant RB cell lines and chemotherapy treated patient tumors compared to non-treated tumors was revealed by Real-Time PCR. Overexpression approaches were performed to analyze the effects of RARα on RB cell viability, apoptosis, proliferation and tumorigenesis. Besides, we addressed the effect of miR-138 overexpression on RB cell chemotherapy resistance. RESULTS: A binding between miR-138 and RARα was shown by dual luciferase reporter gene assay. The study presented revealed that RARα is downregulated in etoposide resistant RB cells, while miR-138 is endogenously upregulated. Opposing RARα and miR-138 expression levels were detectable in chemotherapy pre-treated compared to non-treated RB tumor specimen. Overexpression of RARα increases apoptosis levels and reduces tumor cell growth of aggressive etoposide resistant RB cells in vitro and in vivo. Overexpression of miR-138 in chemo-sensitive RB cell lines partly enhances cell viability after etoposide treatment. CONCLUSIONS: Our findings show that RARα acts as a tumor suppressor in retinoblastoma and is downregulated upon etoposide resistance in RB cells. Thus, RARα may contribute to the development and progression of RB chemo-resistance.

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A Study on UV Filter Chemicals from Annex VII of European Union Directive 76/768/EEC, in the In Vitro 3T3 NRU Phototoxicity Test

Alternatives to Laboratory Animals ◽

10.1177/026119299802600511 ◽

1998 ◽

Vol 26 (5) ◽

pp. 679-708 ◽

Cited By ~ 5

Author(s):

Horst Spielmann ◽

Michael Balls ◽

Jack Dupuis ◽

Wolfgang J. W. Pape ◽

Odile de Silva ◽

...

Keyword(s):

Neutral Red ◽

Optimum Concentration ◽

Alternative Methods ◽

Uv Filter ◽

Eu Directive ◽

Optimum Concentration Range ◽

The Impact ◽

Positive Results

In 1996, the Scientific Committee on Cosmetology of DGXXIV of the European Commission asked the European Centre for the Validation of Alternative Methods to test eight UV filter chemicals from the 1995 edition of Annex VII of Directive 76/768/EEC in a blind trial in the in vitro 3T3 cell neutral red uptake phototoxicity (3T3 NRU PT) test, which had been scientifically validated between 1992 and 1996. Since all the UV filter chemicals on the positive list of EU Directive 76/768/EEC have been shown not to be phototoxic in vivo in humans under use conditions, only negative effects would be expected in the 3T3 NRU PT test. To balance the number of positive and negative chemicals, ten phototoxic and ten non-phototoxic chemicals were tested under blind conditions in four laboratories. Moreover, to assess the optimum concentration range for testing, information was provided on appropriate solvents and on the solubility of the coded chemicals. In this study, the phototoxic potential of test chemicals was evaluated in a prediction model in which either the Photoirritation Factor (PIF) or the Mean Photo Effect (MPE) were determined. The results obtained with both PIF and MPE were highly reproducible in the four laboratories, and the correlation between in vitro and in vivo data was almost perfect. All the phototoxic test chemicals provided a positive result at concentrations of 1μg/ml, while nine of the ten non-phototoxic chemicals gave clear negative results, even at the highest test concentrations. One of the UV filter chemicals gave positive results in three of the four laboratories only at concentrations greater than 100μg/ml; the other laboratory correctly identified all 20 of the test chemicals. An analysis of the impact that exposure concentrations had on the performance of the test revealed that the optimum concentration range in the 3T3 NRU PT test for determining the phototoxic potential of chemicals is between 0.1μg/ml and 10μg/ml, and that false positive results can be obtained at concentrations greater than 100μg/ml. Therefore, the positive results obtained with some of the UV filter chemicals only at concentrations greater than 100μg/ml do not indicate a phototoxic potential in vivo. When this information was taken into account during calculation of the overall predictivity of the 3T3 NRU PT test in the present study, an almost perfect correlation of in vitro versus in vivo results was obtained (between 95% and 100%), when either PIF or MPE were used to predict the phototoxic potential. The management team and participants therefore conclude that the 3T3 NRU PT test is a valid test for correctly assessing the phototoxic potential of UV filter chemicals, if the defined concentration limits are taken into account.

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