Title page for ETD etd-080999-102837

Type of Document Master's Thesis
Author Shang, Xueqin
URN etd-080999-102837
Title Metabolic Studies on 1-Cyclopropyl-4-phenyl-1,2,3,6-tetrahydropyridinyl Derivatives by HPLC and LC-ESI/MS
Degree Master of Science
Department Chemistry
Advisory Committee
Advisor Name Title
Castagnoli, Neal Jr. Committee Chair
Anderson, Mark R. Committee Member
  • cyclopropylaminyl radical cations
  • biotransformation
  • cytochrome P450
  • single electron transfer
  • HPLC
  • LC/MS
Date of Defense 1999-07-28
Availability unrestricted
The MAO-B catalyzed metabolic bioactivation of the parkinsonian inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to generate the neurotoxic 1-methyl-4-phenylpyridinium species (MPP+) is well documented. The N-cyclopropyl analog (CPTP) of MPTP is a mechanism based inactivator of MAO-B which presumably is processed by a single electron transfer (SET) pathway to generate a bioalkylating species. These results have prompted us to study how the cytochromes P450, the major liver drug metabolizing oxidases, interact with N-cyclopropyl analogs of MPTP. HPLC with diode array detection and LC-electrosprary ionization mass spectrometry (LC-ESI/MS) based methods have been developed for metabolite detection and characterization. From the UV spectral data and pseudomolecular ion species observed by LC-ESI/MS, we have identified N-oxide, C-hydroxylated, and pyridinium metabolites. For the trans-1-(2-phenylcyclopropyl) analog, cinnamaldehyde and p-hydroxycinnamaldehyde also were characterized.

Incubation of CPTP and its derivatives with cDNA expressed human hepatic cytochrome P450 has shown that CYP2D6 catalyzes the formation of cinnamaldehyde, the N-descyclopropyl, pyridinium and hydroxylated products. CYP3A4 is responsible for the formation of the N-descyclopropyl and pyridinium species and cinnamaldehyde but it does not mediate any hydroxylation reactions. Since both the a-carbon oxidation and N-descyclopropylation transformations are mediated by a single enzyme (either CYP2D6 or CYP3A4), we propose a common intermediate for both pathways, namely the cyclopropylaminyl radical cation generated by the SET pathway. This intermediate partitions between the a-carbon oxidation pathway leading to the dihydropyridinium and pyridinium species and the ring opening pathway leading to the N-descyclopropyl metabolite and aldehyde species. The phenyl substituent on the cyclopropyl ring stabilizes the ring opened distonic radical cation and favors the ring opening pathway and results in the formation of less of the pyridinium species. The proton and methyl substituents on the cyclopropyl ring favor the a-carbon oxidation pathway and increased amounts of the pyridinium species are formed.

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