2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is selectively toxic to primary dopaminergic neurons in vitro.
Parkinson's disease (PD) is the second most common neurodegenerative disease. Much data has linked the etiology of PD to a variety of environmental factors. The majority of cases are thought to arise from a combination of genetic susceptibility and environmental factors. Chronic exposures to dietary factors, including meat, have been identified as potential risk factors. Although heterocyclic amines that are produced during high-temperature meat cooking are known to be carcinogenic, their effect on the nervous system has yet to be studied in depth. In this study, we investigated neurotoxic effects of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a highly abundant heterocyclic amine in cooked meat, in vitro. We tested toxicity of PhIP and the two major phase I metabolites, N-OH-PhIP and 4'-OH-PhIP, using primary mesencephalic cultures from rat embryos. This culture system contains both dopaminergic and nondopaminergic neurons, which allows specificity of neurotoxicity to be readily examined. We find that exposure to PhIP or N-OH-PhIP is selectively toxic to dopaminergic neurons in primary cultures, resulting in a decreased percentage of dopaminergic neurons. Neurite length is decreased in surviving dopaminergic neurons. Exposure to 4'-OH-PhIP did not produce significant neurotoxicity. PhIP treatment also increased formation of oxidative damage markers, 4-hydroxy-2-nonenal (HNE) and 3-nitrotyrosine in dopaminergic neurons. Pretreatment with N-acetylcysteine was protective. Finally, treatment with blueberry extract, a dietary factor with known antioxidant and other protective mechanisms, prevented PhIP-induced toxicity. Collectively, our study suggests, for the first time, that PhIP is selectively toxic to dopaminergic neurons likely through inducing oxidative stress.
School of Health Sciences, Purdue University, West Lafayette, Indiana 47907 Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907 Cook MED Institute, West Lafayette, Indiana 47906.
Amy M
AM
Griggs
School of Health Sciences, Purdue University, West Lafayette, Indiana 47907.
Zeynep S
ZS
Agim
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907.
Vartika R
VR
Mishra
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907.
Mitali A
MA
Tambe
Chemical/Biological Technologies, Defense Threat Reduction Agency, Fort Belvoir, Virginia 22060.
Alison E
AE
Director-Myska
Biosciences & Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, California 94551.
Kenneth W
KW
Turteltaub
Department of Statistics, Purdue University, West Lafayette, Indiana 47907.
George P
GP
McCabe
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907.
Jean-Christophe
JC
Rochet
School of Health Sciences, Purdue University, West Lafayette, Indiana 47907 cannonjr@purdue.edu.
Jason R
JR
Cannon
D000818:Animals; D000975:Antioxidants / Q000302:isolation & purification / Q000494:pharmacology; D001667:Binding, Competitive; D029798:Blueberry Plants / Q000737:chemistry; D002470:Cell Survival / Q000187:drug effects; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007093:Imidazoles / Q000378:metabolism / Q000633:toxicity*; D008636:Mesencephalon / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D016501:Neurites / Q000187:drug effects / Q000473:pathology; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D018384:Oxidative Stress / Q000187:drug effects; D010936:Plant Extracts / Q000302:isolation & purification / Q000494:pharmacology; D061251:Primary Cell Culture; D017207:Rats, Sprague-Dawley
D000975:Antioxidants; D050483:Dopamine Plasma Membrane Transport Proteins; D007093:Imidazoles; D010936:Plant Extracts; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine
Parkinson's disease; PhIP; heterocyclic amines; neurotoxicity