PMID- 10383923
OWN - NLM
STAT- MEDLINE
DCOM- 19990720
LR  - 20161124
IS  - 0090-9556 (Print)
IS  - 0090-9556 (Linking)
VI  - 27
IP  - 7
DP  - 1999 Jul
TI  - Specific dehydrogenation of 3-methylindole and epoxidation of naphthalene by
      recombinant human CYP2F1 expressed in lymphoblastoid cells.
PG  - 798-803
AB  - 3-Methylindole (3MI) is a naturally occurring pulmonary toxin that requires
      metabolic activation. Previous studies have shown that 3MI-induced pneumotoxicity
      resulted from cytochrome P-450-catalyzed dehydrogenation of 3MI to an
      electrophilic methylene imine (3-methyleneindolenine), which covalently bound to 
      cellular macromolecules. Multiple cytochrome P-450s are capable of metabolizing
      3MI to several different metabolites, including oxygenated products. In the
      present study, the role of human CYP2F1 in the metabolism of 3MI was examined to 
      determine whether it catalyzes dehydrogenation rather than hydroxylation or ring 
      oxidation. Metabolism was examined using microsomal fractions from human
      lymphoblastoid cells that expressed the recombinant human CYP2F1 P-450 enzyme.
      Expression of CYP2F1 in the lymphoblastoid cells proved to be an appropriate
      expression system for this enzyme. Products were analyzed using HPLC and the
      mercapturate, 3-[(N-acetylcystein-S-yl)methyl]indole, of the reactive
      intermediate was identified and quantified. Product analysis showed that human
      CYP2F1 efficiently catalyzed the dehydrogenation of 3MI to the methylene imine
      without detectable formation of indole-3-carbinol or 3-methyloxindole. High
      substrate concentrations of 3MI strongly inhibited production of the
      dehydrogenated product, a result that may indicate the existence of
      mechanism-based inhibition of CYP2F1 by 3MI. Recombinant CYP2F1 demonstrated
      remarkable selectivity for the bioactivation of 3MI to the putative
      dehydrogenated reactive electrophile. Bioactivation of naphthalene to its
      pneumotoxic epoxide by CYP2F1 was also demonstrated.
FAU - Lanza, D L
AU  - Lanza DL
AD  - Department of Pharmacology and Toxicology, University of Utah, Salt Lake City,
      Utah 84112-5820, USA.
FAU - Code, E
AU  - Code E
FAU - Crespi, C L
AU  - Crespi CL
FAU - Gonzalez, F J
AU  - Gonzalez FJ
FAU - Yost, G S
AU  - Yost GS
LA  - eng
GR  - HL13645/HL/NHLBI NIH HHS/United States
GR  - P42-ES-04675-10/ES/NIEHS 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 (Epoxy Compounds)
RN  - 0 (Naphthalenes)
RN  - 0 (Recombinant Proteins)
RN  - 2166IN72UN (naphthalene)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - 9W945B5H7R (Skatole)
RN  - EC 1.14.14.1 (CYP2F1 protein, human)
RN  - EC 1.14.14.1 (Cytochrome P450 Family 2)
RN  - GAN16C9B8O (Glutathione)
SB  - IM
MH  - Cell Line
MH  - Cytochrome P-450 Enzyme System/*metabolism
MH  - Cytochrome P450 Family 2
MH  - Epoxy Compounds/*metabolism
MH  - Glutathione/metabolism
MH  - Humans
MH  - Hydrogenation
MH  - Lymphocytes/*enzymology
MH  - Naphthalenes/*pharmacokinetics
MH  - Recombinant Proteins/metabolism
MH  - Skatole/*pharmacokinetics
MH  - Substrate Specificity
EDAT- 1999/06/29 00:00
MHDA- 1999/06/29 00:01
CRDT- 1999/06/29 00:00
PHST- 1999/06/29 00:00 [pubmed]
PHST- 1999/06/29 00:01 [medline]
PHST- 1999/06/29 00:00 [entrez]
PST - ppublish
SO  - Drug Metab Dispos. 1999 Jul;27(7):798-803.