Use of the photo-micronucleus assay in Chinese hamster V79 cells to study photochemical genotoxicity.

Photochemical genotoxicity can be detected using appropriately adapted versions of most of the standard in vitro genotoxicity assays. The most sensitive approach to detect potentially photogenotoxic agents seems to be the investigation of DNA damage (DNA strand breakage, chromosomal aberrations, micronuclei) in mammalian cells in vitro. In a previous paper, we proposed the use of the micronucleus assay in Chinese hamster V79 cells for this purpose. This assay was found suitable to detect various photogenotoxic compounds with different photoactivation mechanisms. In order to extend the experimental experiences with this assay, we present here further data from a screening mode testing of 16 different potential photosensitizers. The photoclastogenic and photocytotoxic potential of the compounds was investigated concomitantly. So far, all substances detected in the photo-micronucleus assay as photogenotoxins also exhibited photocytotoxic properties but not vice versa. Among the compounds tested in the present study, tiaprofenic acid, 5-MOP, angelicin, nitrazepam, bendroflumethiazide, and dacarbazine were photogenotoxic and photocytotoxic. Further, 6-mercaptopurine, a metabolite of azathioprine was positive for both endpoints, whereas azathioprine was found negative. Azathioprine seems to be an example of a compound which lacks photo(geno)toxic properties in vitro but may be converted to a photosensitizer by enzymatical metabolization. With the results obtained in this study, the data base for the photo-micronucleus assay was extended to 35 compounds, which were tested using the same protocol and the same irradiation conditions. The photogenotoxicity results of all these compounds are summarized and discussed in correlation to their different photoactivation mechanisms, photocytotoxicity and photocarcinogenicity.

[1]  Gary M Williams,et al.  Photochemical mutagenicity of phototoxic and photochemically carcinogenic fluoroquinolones in comparison with the photostable moxifloxacin , 2000, Archives of Toxicology.

[2]  F. Urbach,et al.  Enhancement of experimental photocarcinogenesis by topical retinoic acid. , 1979, Cancer letters.

[3]  S. Sortino,et al.  Molecular mechanisms of photosensitization XIII: a combined differential scanning calorimetry and DNA photosensitization study in non steroidal antiinflammatory drugs-DNA interaction. , 1999, International journal of pharmaceutics.

[4]  M Liebsch,et al.  The International EU/COLIPA In Vitro Phototoxicity Validation Study: Results of Phase II (Blind Trial). Part 1: The 3T3 NRU Phototoxicity Test. , 1998, Toxicology in vitro : an international journal published in association with BIBRA.

[5]  R. Stern,et al.  Malignant melanoma in patients treated for psoriasis with methoxsalen (psoralen) and ultraviolet A radiation (PUVA). The PUVA Follow-Up Study. , 1997, The New England journal of medicine.

[6]  B. Epe,et al.  Wavelength dependence of oxidative DNA damage induced by UV and visible light. , 1997, Carcinogenesis.

[7]  F. Dall'acqua,et al.  Angelicins, angular analogs of psoralens: chemistry, photochemical, photobiological and phototherapeutic properties. , 1991, Pharmacology & therapeutics.

[8]  D. Averbeck,et al.  Genetic effect of 3-carbethoxypsoralen, angelicin, psoralen and 8-methoxypsoralen plus 365-nm irradiation in Saccharomyces cerevisiae: induction of reversions, mitotic crossing-over, gene conversion and cytoplasmic "petite" mutations. , 1979, Mutation research.

[9]  P. Kasper,et al.  The application of the micronucleus test in Chinese hamster V79 cells to detect drug-induced photogenotoxicity. , 1999, Mutation research.

[10]  R. Sik,et al.  PHOTOCHEMICAL SENSITIZATION BY AZATHIOPRINE AND ITS METABOLITES. PART 3. A DIRECT EPR AND SPIN‐TRAPPING STUDY OF LIGHT‐INDUCED FREE RADICALS FROM 6‐MERCAPTOPURINE AND ITS OXIDATION PRODUCTS , 1994, Photochemistry and photobiology.

[11]  P. Glazer,et al.  Mutagenesis by 8-methoxypsoralen and 5-methylangelicin photoadducts in mouse fibroblasts: mutations at cross-linkable sites induced by offoadducts as well as cross-links. , 1995, Cancer research.

[12]  P. Kasper,et al.  Photochemical genotoxicity and photochemical carcinogenesis--two sides of a coin? , 1998, Toxicology letters.

[13]  S. McKiernan,et al.  In vitro micronucleus assay with Chinese hamster V79 cells - results of a collaborative study with in situ exposure to 26 chemical substances. , 2000, Mutation research.

[14]  B. Monk.  Basal cell carcinoma following amiodarone therapy , 1995, The British journal of dermatology.

[15]  G. Marconi,et al.  Photodecarboxylation of Ketoprofen in Aqueous Solution. A Time-resolved Laser-induced Optoacoustic Study¶ , 2000, Photochemistry and photobiology.

[16]  E. Selvaag.  Inhibition of thiazide photohemolysis in vitro by antioxidants and a nitrogen atmosphere , 1996, Photodermatology, photoimmunology & photomedicine.

[17]  M. Miranda,et al.  New Trends in Photobiology (Invited Review) Photosensitizing drugs containing the benzophenone chromophore , 1998 .

[18]  B. Monk.  Amiodarone‐induced photosensitivity and basal‐cell carcinoma , 1990, Clinical and experimental dermatology.

[19]  J. Dresp,et al.  Photomutagenesis test development: II. 8-Methoxypsoralen, chlorpromazine and sunscreen compounds in chromosomal aberration assays using CHO cells. , 1993, Mutation research.

[20]  J. Castell,et al.  Tiaprofenic Acid-photosensitized Damage to Nucleic Acids: A Mechanistic Study Using Complementary in vitro Approaches , 2000, Photochemistry and photobiology.

[21]  D. Moore,et al.  ENHANCEMENT OF UV‐INDUCED SKIN CARCINOGENESIS BY AZATHIOPRINE: ROLE OF PHOTOCHEMICAL SENSITISATION , 1989, Photochemistry and photobiology.

[22]  D. Averbeck,et al.  The Second ECVAM Workshop on Phototoxicity Testing , 2000, Alternatives to laboratory animals : ATLA.

[23]  J. Montastruc,et al.  Photosensitivity to Ketoprofen , 2000, Drug safety.

[24]  S Albertini,et al.  Photomutagenesis test development: I. 8-Methoxypsoralen, chlorpromazine and sunscreen compounds in bacterial and yeast assays. , 1993, Mutation research.

[25]  S. Schauder,et al.  [Photosensitization with DTIC therapy in metastatic malignant melanoma]. , 1980, Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete.

[26]  R. Snyder,et al.  Photogenotoxicity of fluoroquinolones in Chinese hamster V79 cells: dependency on active topoisomerase II. , 1999 .

[27]  F. A. de la Iglesia,et al.  In vitro photogenotoxic activity of clinafloxacin: a paradigm predicting photocarcinogenicity. , 1999, Toxicology and applied pharmacology.

[28]  V. Hemmens,et al.  PHOTOCHEMICAL SENSITIZATION BY AZATHIOPRINE AND ITS METABOLITES—II. AZATHIOPRINE AND NITROIMIDAZOLE METABOLITES , 1986, Photochemistry and photobiology.

[29]  P. Forbes.  Relevance of Animal Models of Photocarcinogenesis to Humans , 1996, Photochemistry and photobiology.

[30]  J. Ferguson,et al.  Photosensitivity due to retinoids: clinical and laboratory studies , 1986, The British journal of dermatology.

[31]  J. Saurat,et al.  Biological Activities of Topical Retinaldehyde , 1999, Dermatology.

[32]  E. Gocke.  Review of the genotoxic properties of chlorpromazine and related phenothiazines. , 1996, Mutation research.

[33]  K. Loveday.  Interrelationship of Photocarcinogenicity, Photomutagenicity and Phototoxicity , 1996, Photochemistry and photobiology.

[34]  A. Castellan,et al.  Photodimerization of anthracenes in fluid solution:structural aspects , 2000 .

[35]  W. von der Hude,et al.  Chemically induced micronucleus formation in V79 cells--comparison of three different test approaches. , 1999, Mutation research.

[36]  P. Kasper,et al.  The Relevance of Photomutagenicity Testing as a Predictor of Photocarcinogenicity , 1998 .

[37]  L. Cerroni,et al.  p53 mutation in squamous cell carcinomas from psoriasis patients treated with psoralen + UVA (PUVA). , 1997, The Journal of investigative dermatology.

[38]  N Chouini-Lalanne,et al.  Nonsteroidal antiinflammatory drug-photosensitized formation of pyrimidine dimer in DNA. , 1998, Biochemical pharmacology.

[39]  M. Fenech,et al.  Report from the In Vitro Micronucleus Assay Working Group , 2003, Mutation research.

[40]  V. Hemmens,et al.  PHOTOCHEMICAL SENSITIZATION BY AZATHIOPRINE AND ITS METABOLITES—I. 6‐MERCAPTOPURINE , 1986, Photochemistry and photobiology.

[41]  K. Kaidbey,et al.  Photosensitizing potential of certain nonsteroidal anti-inflammatory agents. , 1989, Archives of dermatology.

[42]  F. Urbach,et al.  Fluoroquinolone antibacterials enhance UVA-induced skin tumors. , 1997, Journal of photochemistry and photobiology. B, Biology.

[43]  H. Hönigsmann,et al.  Photosensitivity and hyperpigmentation in amiodarone-treated patients: incidence, time course, and recovery. , 1989, The Journal of investigative dermatology.

[44]  A. Jacobs,et al.  Does Photosensitivity Predict Photococarcinogenicity? , 1999 .

[45]  S. Nadadur,et al.  Mutations induced by dacarbazine activated with cytochrome P-450. , 1995, Mutation research.

[46]  R. Snyder,et al.  Considerations on photochemical genotoxicity: Report of the International Workshop on Genotoxicity Test Procedures Working Group , 2000, Environmental and molecular mutagenesis.

[47]  G. Mohn,et al.  RELATIONSHIP BETWEEN STRUCTURE AND PHOTOBIOLOGICAL ACTIVITY OF 7‐NITRO‐1,4‐BENZODIAZEPINES , 1981, Photochemistry and photobiology.

[48]  B. Epe,et al.  Oxidative DNA damage induced by visible light in mammalian cells: extent, inhibition by antioxidants and genotoxic effects. , 1998, Mutation research.

[49]  B. Eberlein-König,et al.  Phototoxicity of non-steroidal anti-inflammatory drugs: in vitro studies with visible light. , 1996, Acta dermato-venereologica.

[50]  H. Ananthaswamy,et al.  Signature p53 mutation at DNA cross-linking sites in 8-methoxypsoralen and ultraviolet A (PUVA)-induced murine skin cancers. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[51]  A. DeCaprio.  The toxicology of hydroquinone--relevance to occupational and environmental exposure. , 1999, Critical reviews in toxicology.

[52]  S Albertini,et al.  The photomutagenicity of fluoroquinolones and other drugs. , 1998, Toxicology letters.

[53]  S Albertini,et al.  The photomutagenicity of fluoroquinolones in tests for gene mutation, chromosomal aberration, gene conversion and DNA breakage (Comet assay). , 1996, Mutagenesis.

[54]  R. Dunmore,et al.  Development of assays for the detection of photomutagenicity of chemicals during exposure to UV light—I. Assay development , 1991 .

[55]  J. McNiff,et al.  Psoralen photochemotherapy, clinical efficacy, and photomutagenicity: The role of molecular epidemiology in minimizing risks , 1998, Environmental and molecular mutagenesis.

[56]  J. Piette,et al.  MECHANISM OF DNA CLEAVAGE MEDIATED BY PHOTOEXCITED NON‐STEROIDAL ANTIINFLAMMATORY DRUGS , 1991, Photochemistry and photobiology.