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(Received for publication, December 30, 1996, and in revised form, April 14, 1997)
From the Department of Pharmacology and Molecular Toxicology,
University of Massachusetts Medical Center,
Worcester, Massachusetts 01655
The cytochrome P-4501A1 (CYP1A1) gene is
regulated by several trans-acting factors including the 4 S polycyclic
aromatic hydrocarbon (PAH)-binding protein, which has recently been
identified as glycine N-methyltransferase (GNMT) (Raha, A.,
Wagner, C., Macdonald, R. G., and Bresnick, E. (1994)
J. Biol. Chem. 269, 5750-5756). The role of GNMT as a
4 S PAH-binding protein in mediating the induction of cytochrome
P-4501A1 has been investigated further. GNMT cDNA, which was cloned
into a pMAMneo vector containing the Rous sarcoma virus promoter and
the neomycin resistance gene, was stably transfected into D422 Chinese
hamster ovary (CHO) cells. Several positive clones were selected by
reverse transcription-polymerase chain reaction and assayed for the
expression of recombinant protein. Western blot analysis indicated the
expression of significant levels of the 4 S protein in the stably
transfected CHO cells (CHO-GNMT). Cytosolic preparations from the
CHO-GNMT showed high benzo[a]pyrene (B[a]P) binding but no
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) binding activity when
compared with clones transfected with the pMAMneo vector alone
(CHO-neo) or the parental CHO cells. Challanging the CHO-GNMT cells
with 4 µM B[a]P resulted in elevated levels of CYP1A1
mRNA. Equally effective in inducing CYP1A1 mRNA were
benzo[e]pyrene and 3-methylcholanthrene. On the other hand, TCDD did
not induce CYP1A1 gene expression in these cells. B[a]P-treated CHO-GNMT, expressing the 4 S protein, also showed CYP1A1 protein by
Western blotting and exhibited ethoxyresorufin-O-deethylase activity; neither the CHO-neo or parental CHO cells were positive for
any of these measures. No Ah receptor message or protein was detectable
in the parental CHO, CHO-neo, or CHO-GNMT cells. Furthermore, no XRE
binding activity was observed in TCDD-treated cytosolic preparations or
nuclear extracts from CHO-GNMT cells that were treated with TCDD. These
studies unequivocally establish that GNMT is a PAH-binding protein that
can mediate the induction of CYP1A1 by PAHs such as B[a]P through an
Ah receptor-independent pathway.
Volume 272, Number 34,
Issue of August 22, 1997
pp. 21221-21226
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
ROLE AS A POLYCYCLIC AROMATIC HYDROCARBON-BINDING RECEPTOR
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