The in vitro and in vivo genotoxicity of isotretinoin assessed by cytokinesis blocked micronucleus assay and comet assay

• Published in: Toxicology in vitro Vol. 27; no. 2; pp. 900 - 907
• Main Authors: Silva, F.S.G., Oliveira, H., Moreiras, A., Fernandes, J.C., Bronze-da-Rocha, E., Figueiredo, A., Custódio, J.B.A., Rocha-Pereira, P., Santos-Silva, A.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.03.2013
• Subjects: Acne Vulgaris - drug therapy; Acne Vulgaris - radiotherapy; Adult; Apoptosis - drug effects; Cells, Cultured; Combined Modality Therapy; Comet Assay; Cytokinesis; Dermatologic Agents - toxicity; Female; Genotoxicity; Humans; Isotretinoin; Isotretinoin - toxicity; Lymphocytes - drug effects; Lymphocytes - metabolism; Male; Micronucleus; Micronucleus Tests; Narrowband ultraviolet B; Necrosis - chemically induced; Psoriasis - drug therapy; Psoriasis - radiotherapy; Ultraviolet Rays; MN; Narrowband ultraviolet B; CBPI; NBUVB; Genotoxicity; PHA; BN; EDTA; Comet assay; RA; FBS; RARs; TBE; Micronucleus; TL; TM; Isotretinoin; CBMN
• ISSN: 0887-2333; 1879-3177
• DOI: 10.1016/j.tiv.2013.01.002

► We evaluated the genotoxic effects of isotretinoin alone or combined with NBUVB. ► Isotretinoin alone has no mutagenic potential. ► For Isotretinoin+NBUVB further studies are needed to clarify their mutagenic potential. ► Isotretinoin reduces the lymphocyte proliferation, by inducing apoptosis and necrosis. Isotretinoin is a retinoic acid frequently used in monotherapy or combined with narrow-band ultraviolet B (NBUVB) irradiation to treat patients with acne and psoriasis vulgaris. As both diseases need frequent and/or prolonged therapeutic interventions, the study of the genotoxicity of retinoids becomes important. Our aim was to study the genotoxic effects of isotretinoin alone or combined with NBUVB. In vitro studies were performed in the absence of S9 metabolic activation using blood from five healthy volunteers, incubated 72h with isotretinoin (1.2–20μM) (i.e., at concentrations usually achieved in blood with therapeutic doses as well as at higher concentrations). In vivo studies were also performed using blood from two patients with acne and three patients with psoriasis vulgaris treated with isotretinoin in monotherapy (8 or 20mg/day) or combined with NBUVB (20mg isotretinoin/day+NBUVB). The genotoxic effect was evaluated by the cytokinesis-blocked micronucleus and the comet assays. Our studies showed that isotretinoin alone was not genotoxic when tested in human lymphocytes in vitro and in vivo. There was no clear genotoxic effect in psoriatic patients treated with isotretinoin and NBUVB. The in vitro studies showed that isotretinoin induced apoptosis and necrosis in human lymphocytes at higher doses.