Enhancement of cytotoxicity and clastogenicity of l-DOPA and dopamine by manganese and copper.
It is an increasingly popular hypothesis that the continued degeneration of dopaminergic neurons in Parkinson's disease (PD) may be the consequence of aberrant oxidation of dopamine and resultant generation of DNA reactive species in PD patients receiving levodopa (l-DOPA) therapy. Occupational metal exposure, particularly to manganese, is a risk factor for Parkinsonism and manganese has been shown to be a true catalyst for dopamine oxidation lending support to this hypothesis. In the present studies, we demonstrate that the antiproliferative activity of l-DOPA and dopamine on Chinese Hamster V79 cells is enhanced by at least an order of magnitude by concomitant exposure to manganese chloride or copper sulfate (500 microM), but not to iron(III) or zinc. Moreover, manganese and copper confer strong clastogenic properties to both compounds as detected in an in vitro micronucleus assay in V79 cells. Metal catalyzed oxidation of drug was associated with the development of a brown-black particulate substance presumed to be a melanin precursor formation. The extent of formation of this precursor paralleled clastogenicity. Metal-enhanced effects were completely antagonized by the concurrent addition of cysteine or reduced glutathione to the cultures. These findings are in support of the hypothesis that aberrant oxidation of dopamine resulting from non-physiological levels of catalytic metals may contribute to the death of dopaminergic neurons and further suggest that oxidation-dependent DNA damage may be the basis for this cell death.
Snyder
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RD
Abbott Laboratories, Dept. 468. AP-13A, 100 Abbott Park Rd., Abbott Park, IL 60064, USA. snyder.ronald@igate.abbott.com
Friedman
M B
MB
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003300:Copper / Q000494:pharmacology*; D006224:Cricetinae; D003545:Cysteine / Q000494:pharmacology; D004298:Dopamine / Q000633:toxicity*; D005978:Glutathione / Q000494:pharmacology; D007980:Levodopa / Q000633:toxicity*; D008168:Lung / Q000187:drug effects; D008345:Manganese / Q000494:pharmacology*; D008543:Melanins / Q000378:metabolism; D015162:Micronucleus Tests; D009153:Mutagens / Q000633:toxicity*; D010300:Parkinson Disease / Q000503:physiopathology
D008543:Melanins; D009153:Mutagens; D008345:Manganese; D007980:Levodopa; D003300:Copper; D005978:Glutathione; D003545:Cysteine; D004298:Dopamine