Enhanced Expression of Rat Hepatic CYP3A1 and 3A2 by Pyridine (PY)
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Authors
Cibor, Gregory M.
Issue Date
1993
Type
Thesis
Language
en_US
Keywords
Alternative Title
Abstract
Cytochrome P450s (CYPs) are monoxygenases, primarily found in
hepatic microsomes, which play major roles in the metabolism of numerous
xenobiotics and physiological-occurring compounds. However, it has been
reported that elevated levels of CYPs may predispose cells to carcinogenic
events, cell death or cell mutation. In particular, CYP3A1 and 3A2 are
responsible for the metabolism of a variety of hormones, antibiotics and
procarcinogens. Consequently, elevated levels of CYP3A 1/3A2 may initiate
carcinogenesis, disrupt hormonal balance andlor render oral contraceptives
ineffective. Pyridine (PY) is a constituent of tobacco and tobacco smoke and the
PY moiety is present in several therapeutic agents. Previous studies reported
that PY induced levels of CYP 1 A 1/2, 28112 and 2E 1. The effects of pyridine on
CYP3A 1 and 3A2 expression in rat liver have been examined by enzymatic
activity assays and immunoblot analyses. The molecular basis of induction was
characterized by Northern blot hybridization analyses using oligonucleotide
probes specific for 3A1 or 3A2 mRNA. Erythromycin N-demethylase activity was
elevated -4-fold over controls folIowing treatment with 400 mg PY /kg/day for 3
days. CYP3A 1/3A2 protein levels were elevated -3-fold over controls following
treatment with 400 mg PY/kg/day for 3 days. Dexamethasone (5 mg/kg/day for
4 days) and phenobarbital (100 mg/kg/day for 3 days) treatments elevated both
erythromycin N-demethylase activity and 3A 1/3A2 protein levels 2- and 3-fold,
respectively. Northern blot analysis revealed that 3A 1 poly(A)+ RNA levels
rapidly increased following treatment with high-dose PY (200 mg/kg/day for 3
days), whereas the 3A2 poly(A)+ RNA levels only slightly increased following
treatment with high-dose PY. Phenobarbital treatment (100 mg/kg/day for 3
days) induced both 3A 1 and 3A2 poly(A)+ RNA expression, whereas
dexamethasone treatment (5 mg/kg/day for 4 days) induced 3A 1 poly(A)+ RNA
expression only. These results suggest that 3A 1 and 3A2 induction by PY
occurs primarily as a result of increased mRNA levels. Supported by NIH grant
ES05577 (H. K.), CA16954 (P. F. H.) and ES03656 (R. F. N.).
Description
vi, 34 p.
Citation
Publisher
Kalamazoo College
License
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