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Titolo:
Direct analysis of mitochondrial toxicity of antiretroviral drugs
Autore:
Foli, A; Benvenuto, F; Piccinini, G; Bareggi, A; Cossarizza, A; Lisziewicz, J; Lori, F;
Indirizzi:
IRCCS Policlin S Matteo, RIGHT, I-27100 Pavia, Italy IRCCS Policlin S Matteo Pavia Italy I-27100 RIGHT, I-27100 Pavia, Italy IRCCS Policlin S Matteo, RIGHT, Washington, DC USA IRCCS Policlin S Matteo Washington DC USA teo, RIGHT, Washington, DC USA IRCCS Policlin S Matteo, Biotechnol Lab, Pavia, Italy IRCCS Policlin S Matteo Pavia Italy atteo, Biotechnol Lab, Pavia, Italy Sect Gen Pathol, Dept Biol Sci, Modena, Italy Sect Gen Pathol Modena Italy t Gen Pathol, Dept Biol Sci, Modena, Italy
Titolo Testata:
AIDS
fascicolo: 13, volume: 15, anno: 2001,
pagine: 1687 - 1694
SICI:
0269-9370(20010907)15:13<1687:DAOMTO>2.0.ZU;2-Z
Fonte:
ISI
Lingua:
ENG
Soggetto:
IMMUNODEFICIENCY-VIRUS INFECTION; PERIPHERAL-BLOOD LYMPHOCYTES; HUMAN DNA-POLYMERASES; REVERSE-TRANSCRIPTASE; HIV-INFECTION; CYTOFLUOROMETRIC ANALYSIS; NUCLEOSIDE ANALOGS; SELECTIVE ACTION; DIDANOSINE; HYDROXYUREA;
Keywords:
mitochondria; toxicity; FACS; combination therapy; reverse transcriptase inhibitors;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
51
Recensione:
Indirizzi per estratti:
Indirizzo: Lori, F IRCCS Policlin S Matteo, RIGHT, I-27100 Pavia, Italy IRCCS Policlin S Matteo Pavia Italy I-27100 I-27100 Pavia, Italy
Citazione:
A. Foli et al., "Direct analysis of mitochondrial toxicity of antiretroviral drugs", AIDS, 15(13), 2001, pp. 1687-1694

Abstract

Objectives: Mitochondrial toxicity is a serious side-effect of antiretroviral drugs, especially nucleoside reverse transcriptase inhibitors (NRTI). An in vitro assay to predict mithocondrial toxicity of in-use and developmental NRTI would be invaluable. To test the ability of a cytofluorimetric technique to predict the mitochondrial-dependent pancreatic and hepatic toxicity we used didanosine (ddl) alone or in combination with hydroxyurea (HU). Methods: The technique is based on the ability of the lipophilic cation JC-1 to enter selectivrly into mitochondria and change its colour as the membrane potential changes due to toxicity. Mitochondrial toxicity by HU and ddl was evaluated in pancreatic and hepatic human cell lines. The results were expressed as mitochondrial toxicity index (MTI), ranging from 0 to 100: the negative control was 0 and 100 indicating maximal toxicity. Results: Dose-dependent pancreatic toxicity of ddl was evident after 14 days of culture (MTI 34 +/- 4 at 100 muM, 10 +/- 4 at 10 muM, 2 +/- 3 at 1 muM ddl). HU alone was not toxic (MTI 7 +/- 10 at 100 muM, 2 +/- 2 at 50 muM and 2 +/- 4 at 10 muM HU); however, HU increased the toxicity of high, but not low, concentrations of ddl. For example, the MTI of 10 muM ddl plus 50 muM HU was 54 +/- 9. Negligible mitochondrial toxicity was observed in the hepatic cell line exposed to ddl alone or in combination with HU. Conclusions: This in vitro assay might have in vivo relevance. First, ddl-related pancreatitis is dose dependent, and is reported more frequently than hepatic failure, consistent with our in vitro results. Second, patients who developed pancreatitis during randomized, controlled trials were treatedwith HU in combination with 400 mg ddl once daily (high peak concentrationof ddl in the blood). In contrast, no pancreatitis was observed when HU was combined with 200 mg ddl twice daily (low peak concentration of ddl). These in vivo results are consistent with our in vitro observation that HU increases pancreatic cell toxicity in the presence of high concentrations of ddl. The in vitro assay described here might be used to predict the mitochondrial toxicity of other NRTI, alone or in combination. (C) 2001 Lippincott Williams & Wilkins.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 06/04/20 alle ore 08:11:11