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Vol. 27, Issue 2, 233-239, February 1999
Department of Anatomy and Cell Biology, Queen's University,
Kingston, Ontario, Canada
We tested the hypothesis that vinyl carbamate (VC) is metabolized
in vitro by cytochrome P-450 and carboxylesterase enzymes in murine
lung. Incubations with VC and an NADPH-generating system produced a
50% decrease in N-nitrosodimethylamine (NDMA)
demethylation and a corresponding loss in the amounts of
immunodetectable CYP2E1. Preincubation of microsomes with a CYP2E1
inhibitory antibody or the CYP2E1-selective inhibitor diallyl sulfone
(DASO2) inhibited demethylase activity; no alterations were
detected upon subsequent exposure to VC. Carboxylesterase-mediated
hydrolysis of p-nitrophenyl acetate was reduced by 22%
in microsomes incubated with VC. Decreased carboxylesterase activity
also was detected in microsomes incubated with phenylmethylsulfonyl
fluoride (PMSF), an inhibitor of hydrolase A, a carboxylesterase
isozyme. No change in enzyme activity was detected when microsomes were
subsequently incubated with VC. The loss in carboxylesterase activity
correlated with decreased immunodetectable hydrolase A in microsomes
incubated with VC, PMSF, or PMSF and VC. The reduction in VC-induced
NDMA demethylase activity was increased to 85% of the control in
microsomes previously incubated with PMSF, and this corresponded with a
marked decrease in CYP2E1 immunoreactivity in the immunoblots. Covalent
binding of VC to proteins was detected in microsomes incubated with VC and an NADPH-generating system. Binding was inhibited in microsomes preincubated with either an inhibitory CYP2E1 antibody or
DASO2. In contrast, binding levels were augmented in
microsomes preincubated with PMSF. These data supported VC metabolism
by CYP2E1 and hydrolase A in murine lung microsomes and is consistent
with involvement of CYP2E1 and hydrolase A in the activation and
detoxication of VC, respectively.
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