On the mechanisms underlying 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity. II. Susceptibility among mammalian species correlates with the toxin's metabolic patterns in brain microvessels and liver.
Systemic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes parkinsonism in humans and other primates, but not in rats; mice are intermediate in their susceptibility which varies among strains. We hypothesized previously that the rat's resistance to systemic MPTP toxicity is likely due to the unique enrichment of its blood-brain barrier with enzymes that metabolize MPTP. MPTP metabolites, such as 1-methyl-4-phenylpyridinium (MPP+) and 1-methyl-4-phenyl-2,3-dihydropyridinium, may have difficulty in traversing biological membranes and reaching the brain sites of toxicity. We tested this hypothesis by studying MPTP metabolism: 1) in vitro, by human, rat and mouse brain microvessels and 2) in vivo, in the brain and liver of Wistar rats and two strains of mice known to react differently to systemic MPTP. We found that rat brain microvessels were very efficient at converting MPTP to MPP+ and that this conversion was abolished by pargyline. Microvessels from C57 black mice, which are more sensitive to MPTP toxicity than CF1 white mice, were less capable of metabolizing MPTP to MPP+. Human microvessels were least capable of producing MPP+. In vivo metabolism of MPTP in Wistar rats and the two strains of mice showed that the clearance of MPTP and its metabolites from the brains was most rapid in rats, intermediate in white mice and slowest in black mice. On the other hand, liver metabolism of MPTP by the three groups of animals showed a high rate of MPTP metabolism to a compound(s) other than MPP+ in rats, and a lower rate in mice.(ABSTRACT TRUNCATED AT 250 WORDS)
Riachi
N J
NJ
Department of Neurology, Case Western Reserve University, Cleveland, Ohio.
Harik
S I
SI
Kalaria
R N
RN
Sayre
L M
LM
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015655:1-Methyl-4-phenylpyridinium; D000818:Animals; D001921:Brain / Q000098:blood supply / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000378:metabolism; D011725:Pyridines / Q000378:metabolism* / Q000633:toxicity; D011726:Pyridinium Compounds / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity
D011725:Pyridines; D011726:Pyridinium Compounds; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015655:1-Methyl-4-phenylpyridinium