Enzyme-catalyzed bioactivation of cyclic tertiary amines to form potential neurotoxins.
The pyridinium metabolites formed in the MAO-B catalyzed oxidation of 1-methyl-4-substituted-1,2,3,6-tetrahydropyridinyl derivatives, such as the parkinsonian inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), cause the selective degeneration of nigrostriatal neurons, presumably by inhibition of mitochondrial respiration and depletion of ATP stores. The possibility that other partially oxidized piperidinyl derivatives also may be biotransformed to toxic pyridinium metabolites has led us to examine the metabolic fate of the neuroleptic agent haloperidol (HP) and its tetrahydropyridinyl dehydration product 4-(4-chlorophenyl)-1[4-(4-fluorophenyl)-4-oxobutyl]- 1,2,3,6-tetrahydropyridine (HPTP). In vitro metabolic studies employing tissue preparations isolated from rodents, baboons and humans have documented that cytochrome P4503A enzymes catalyze the biotransformation of both HP and HPTP to yield the corresponding pyridinium metabolite HPP+. An analogous biotransformation profile has been observed with "reduced haloperidol" (RHP), an abundant, circulating metabolite of HP formed by the stereospecific reduction of the benzoyl carbonyl group of HP. In vivo studies also have documented these pathways in humans, baboons and rodents. Although both HPP+ and RHPP+ are found in the urine and plasma of HP treated patients and HP or HPTP treated baboons, attempts to identify an MPTP-type lesion in baboons following long-term treatment with HPTP have failed. On the other hand, evidence for a lesion of the nucleus basalis of Meynert has been obtained. Additionally, the urinary excretion of abnormal organic acids and acylcarnitine conjugates suggests that HP and/or metabolites derived from HP interfere with energy production pathways.
Castagnoli
N
N
Department of Chemistry, Virginia Tech, Blacksburg 24061-0212, USA.
Castagnoli
K P
KP
Van der Schyf
C J
CJ
Usuki
E
E
Igarashi
K
K
Steyn
S J
SJ
Riker
R R
RR
D000588:Amines / Q000378:metabolism*; D000818:Animals; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology; D006220:Haloperidol / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D020267:MPTP Poisoning; D009422:Nervous System Diseases / Q000139:chemically induced*; D009498:Neurotoxins / Q000096:biosynthesis*; D011726:Pyridinium Compounds / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000588:Amines; D018492:Dopamine Antagonists; D009498:Neurotoxins; D011726:Pyridinium Compounds; D003577:Cytochrome P-450 Enzyme System; D006220:Haloperidol