B. Schilter et Cj. Omiecinski, REGIONAL DISTRIBUTION AND EXPRESSION MODULATION OF CYTOCHROME-P-450 AND EPOXIDE HYDROLASE MESSENGER-RNAS IN THE RAT-BRAIN, Molecular pharmacology, 44(5), 1993, pp. 990-996
In the present study, we developed a very sensitive, semiquantitative
assay based on the reverse transcriptase-coupled polymerase chain reac
tion to measure, in a region-selective manner, mRNA expression pattern
s within the brain for microsomal epoxide hydrolase and several cytoch
rome P-450s (P-450s) known to be induced by prototypic agents in other
tissues. The P-450s assessed included the polyaromatic hydrocarbon-in
ducible CYP1A1 and CYP1A2 systems, together with the phenobarbital-ind
ucible P-450s, CYP2B1, CYP2B2, CYP3A1, which were examined 1 8 hr afte
r a single intraperitoneal dose of the respective inducing agents. Hig
hly region-specific patterns of expression were evident for P-450 mRNA
s within the rat brain. In the control, uninduced brain, CYP1A1 mRNAs
were readily detected in the striatum and in the hypothalamus, and to
a lesser extent in the other regions examined. The regional pattern of
expression was similar for CYP1A2; however, a major difference was no
ted in the olfactory bulbs, characterized by a relatively high level o
f CYP1A2 mRNA but correspondingly low levels of CYP1A1. Within the bra
in regions examined, the highest content of CYP2B1 and CYP2B2 mRNAs we
re present in the striatum and in the cerebellum, whereas CYP3A1 level
s varied only slightly across the respective regions. In contrast to t
he P-450s, microsomal epoxide hydrolase mRNAs were expressed at relati
ve homogeneous amounts throughout the brain. Beta-Naphthoflavone marke
dly increased the CYP1A1 and CYP1A2 mRNA contents of each brain region
investigated, although this agent did not affect levels of epoxide hy
drolase. At 18 hr post-treatment with phenobarbital, an optimal time p
eriod for hepatic induction, brain expression was characterized by a c
omplex pattern of effects, with increased levels noted for CYP2B1 mRNA
content in the medulla oblongata, midbrain, and cortex, but decreased
contents measured in the cerebellum, the hypothalamus, and the striat
um. In each of these respective regions, CYP2B2 content was profoundly
decreased whereas epoxide hydrolase expression was slightly increased
by the same treatment. These results establish that the central nervo
us system actively expresses a number of different biotransformation g
ene products in a regional specific and inducer-dependent manner, and
suggest that for tissues exhibiting low regenerative capacity, like th
e brain, such reactions are likely to be of critical toxicological sig
nificance.