PMID- 2891481
OWN - NLM
STAT- MEDLINE
DCOM- 19880210
LR  - 20161123
IS  - 0090-9556 (Print)
IS  - 0090-9556 (Linking)
VI  - 15
IP  - 5
DP  - 1987 Sep-Oct
TI  - Mechanism-based inhibition of cytochrome P-450 by heterocyclic analogues of 
      phencyclidine.
PG  - 648-52
AB  - Three homologues of 1-(1-phenylcyclohexyl)piperidine (PCP) containing the five-, 
      six-, and seven-membered heterocyclic ring (1-(1-phenylcyclohexyl)pyrrolidine 
      (PCPY), PCP, 1-(1-phenylcyclohexyl)hexamethyleneimine (PCHMI) were preincubated 
      with microsomes from phenobarbital-induced rabbit liver. The microsomes were then 
      diluted, an additional charge of NADPH was added, and N-demethylation of 
      benzphetamine was determined. Preincubation of the microsomes with the analogues 
      lowered P-450-dependent N-demethylation by a process that was NADPH-dependent, 
      reduced CO binding to microsomes, and followed pseudo-first order kinetics. The 
      relative rates of inactivation, PCP greater than or equal to PCPY greater than 
      PCHMI, agreed with the order of inhibition of CO binding to reduced microsomes. 
      This mechanism-based inhibition was not observed with phenylcyclohexylamine, 
      indicating that the substituted nitrogen is necessary. The substituted nitrogen 
      must also be part of a heterocyclic ring since the diethylamino analogue of PCP 
      did not exhibit the same type of inhibition a heterocyclic ring is involved. 
      These trends correlated with the expected relative stabilities of the cyclic form 
      of the carbinolamine suggesting that the inhibitory species was formed from the 
      closed ring isomer.
FAU - Brady, J F
AU  - Brady JF
AD  - UCLA Medical Center, Dept. of Pharmacology 90024-1735.
FAU - Dokko, J
AU  - Dokko J
FAU - Di Stefano, E W
AU  - Di Stefano EW
FAU - Cho, A K
AU  - Cho AK
LA  - eng
GR  - DA 02411/DA/NIDA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Drug Metab Dispos
JT  - Drug metabolism and disposition: the biological fate of chemicals
JID - 9421550
RN  - 0 (Cyanides)
RN  - 0 (Cytochrome P-450 Enzyme Inhibitors)
RN  - 0 (Enzyme Inhibitors)
RN  - 0M3S43XK27 (Benzphetamine)
RN  - 2201-39-0 (1-(1-phenylcyclohexyl)pyrrolidine)
RN  - 2808-81-3 (1-(1-phenylcyclohexyl)hexamethyleneimine)
RN  - 7U1EE4V452 (Carbon Monoxide)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - EC 1.14.14.1 (benzphetamine N-demethylase)
RN  - EC 1.5.- (Oxidoreductases, N-Demethylating)
RN  - J1DOI7UV76 (Phencyclidine)
SB  - IM
MH  - Animals
MH  - Benzphetamine/metabolism
MH  - Carbon Monoxide/metabolism
MH  - Chemical Phenomena
MH  - Chemistry, Physical
MH  - Cyanides/pharmacology
MH  - *Cytochrome P-450 Enzyme Inhibitors
MH  - Cytochrome P-450 Enzyme System
MH  - Enzyme Inhibitors/*pharmacology
MH  - Male
MH  - Microsomes, Liver/enzymology
MH  - Oxidoreductases, N-Demethylating/metabolism
MH  - Phencyclidine/*analogs & derivatives/pharmacology
MH  - Rabbits
MH  - Structure-Activity Relationship
EDAT- 1987/09/01 00:00
MHDA- 1987/09/01 00:01
CRDT- 1987/09/01 00:00
PHST- 1987/09/01 00:00 [pubmed]
PHST- 1987/09/01 00:01 [medline]
PHST- 1987/09/01 00:00 [entrez]
PST - ppublish
SO  - Drug Metab Dispos. 1987 Sep-Oct;15(5):648-52.