Toxicokinetics and toxicodynamics of paraquat accumulation in mouse brain.
Paraquat (PQ) is a potential human neurotoxicant and is used in models of oxidative stress. We determined the toxicokinetics (TK) and toxicodynamics (TD) of PQ in adult mouse brain following repeated or prolonged PQ exposure. PQ accumulated in different brain regions and reached a plateau after approximately 18 i.p. (10 mg/kg) doses and resulted in modest morbidity and mortality unpredictably associated with dose interval and number. PQ had divergent effects on horizontal locomotor behavior depending on the number of doses. PQ decreased striatal dopamine levels after the 18th to 36th i.p. dose (10 mg/kg) and reduced the striatal level of tyrosine hydroxylase. Drinking water exposure to PQ (0.03- 0.05 mg/ml) did not result in any mortality and resulted in concentration and time dependent levels in the brain. The brain half-life of PQ varied with mouse strain. PQ accumulates and may saturate a site in mouse brain resulting in complex PQ level and duration-related consequences. These findings should alter our risk assessment of this compound and demonstrate a useful, but complex dynamic model for understanding the consequences of PQ in the brain.
Prasad
Kavita
K
Department of Pathology and Lab Medicine, Robert Wood Johnson Medical School (RWJMS), University of Medicine and Dentistry New Jersey (UMDNJ), Piscataway, NJ 08854, USA.
Tarasewicz
Elizabeth
E
Mathew
Jason
J
Strickland
Pamela A Ohman
PA
Buckley
Brian
B
Richardson
Jason R
JR
Richfield
Eric K
EK
D000704:Analysis of Variance; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D001923:Brain Chemistry / Q000187:drug effects; D002395:Catecholamines / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004333:Drug Administration Routes; D006540:Herbicides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D010269:Paraquat / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D011897:Random Allocation; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D002395:Catecholamines; D006540:Herbicides; D014446:Tyrosine 3-Monooxygenase; D010269:Paraquat