Aspirin-like drugs can protect human T lymphocytes against benzoquinone cytotoxicity: evidence for a NAD(P)H:quinone reductase-dependent mechanism.
Benzene toxicity towards lymphocytes is thought to be mediated by metabolites of benzene including benzoquinone (BQ). NAD(P)H:quinone reductase (QR) is known to protect against BQ toxicity. The expression of the QR gene is regulated by the transcription factor AP-1. We had previously found that aspirin-like drugs (ALD) induce AP-1 in human T lymphocytes. It was therefore hypothesized that ALD would protect lymphocytes against BQ toxicity by inducing QR. Molt-4 cells (M4), a human T lymphocyte cell line, were incubated with different concentrations of two ALD, flurbiprofen and sodium diclofenac, and then exposed to BQ. Toxicity was measured by viability (trypan blue exclusion). Both drugs protected the cells against BQ cytotoxicity in a dose-dependent manner, e.g., sodium diclofenac at 15 microM reduced the fraction of BQ-treated dead cells by 70%. ALDs induced QR activity in the M4 cells in the same range of concentrations that protected the cells against BQ toxicity. The protective effect of ALD was significantly reduced by dicoumarol, a QR-specific inhibitor. Since human T cells and T cell lines do not metabolize arachidonic acid, our data suggest that ALD can protect human T lymphocytes against a metabolite of benzene by induction of QR activity.
Flescher
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E
Nelson Institute of Environmental Medicine, New York University Medical Center, Tuxedo 10987, USA.
Snyder
C A
CA
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016227:Benzoquinones / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects*; D002460:Cell Line; D004008:Diclofenac / Q000494:pharmacology; D001728:Dicumarol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005480:Flurbiprofen / Q000494:pharmacology; D006801:Humans; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects*; D018808:Transcription Factor AP-1 / Q000235:genetics
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016227:Benzoquinones; D018808:Transcription Factor AP-1; D004008:Diclofenac; C004532:quinone; D005480:Flurbiprofen; D001728:Dicumarol; D016660:NAD(P)H Dehydrogenase (Quinone)