Journal Article

Human Prostaglandin H Synthase (hPHS)-1 and hPHS-2 in Amphetamine Analog Bioactivation, DNA Oxidation, and Cytotoxicity

Annmarie Ramkissoon and Peter G. Wells

in Toxicological Sciences

Volume 120, issue 1, pages 154-162
Published in print March 2011 | ISSN: 1096-6080
Published online December 2010 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfq377
Human Prostaglandin H Synthase (hPHS)-1 and hPHS-2 in Amphetamine Analog Bioactivation, DNA Oxidation, and Cytotoxicity

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Neurotoxicity of the amphetamine analogs methamphetamine (METH) and 3,4-methylenedioxyamphetamine (MDA) (the active metabolite of ecstasy) may involve their prostaglandin H synthase (PHS)-dependent bioactivation to free radical intermediates that generate reactive oxygen species and oxidatively damage cellular macromolecules. We used Chinese hamster ovary-K1 (CHO-K1) cell lines either untransfected or stably expressing human PHS-1 (hPHS-1) or hPHS-2 to investigate hPHS isozyme-dependent oxidative damage and cytotoxicity. Both METH and MDA (250–1000μM) caused concentration-independent cytotoxicity in hPHS-1 cells, suggesting maximal bioactivation at the lowest concentration. In hPHS-2 cells, with half the activity of hPHS-1 cells, METH (250–1000μM) cytotoxicity was less than that for hPHS-1 cells but was concentration dependent and increased by exogenous arachidonic acid (AA), which increased hPHS activity. Whereas 10μM MDA and METH were not cytotoxic, at 100μM both analogs caused AA-dependent and concentration-dependent increases in cytotoxicity and DNA oxidation in both hPHS-1/2 cells. The hPHS-2 isozyme appeared to provide more efficacious bioactivation of these amphetamine analogs. Acetylsalicylic acid, an irreversible inhibitor of both hPHS-1 and hPHS-2, blocked cytotoxicity and DNA oxidation in both cell lines and untransfected CHO-K1 cells lacking PHS activity were similarly resistant. Accordingly, isozyme-dependent hPHS-catalyzed bioactivation of METH and MDA can cause oxidative macromolecular damage and cytotoxicity, which may contribute to their neurotoxicity.

Keywords: methamphetamine; ecstasy; prostaglandin H synthase; reactive oxygen species; free radicals; cytotoxicity

Journal Article.  5344 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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