Jw. Hamilton et al., PREFERENTIAL ALTERATION OF INDUCIBLE GENE-EXPRESSION IN-VIVO BY CARCINOGENS THAT INDUCE BULKY DNA LESIONS, Molecular carcinogenesis, 8(1), 1993, pp. 34-43
Our laboratory is interested in whether chemical carcinogen-induced DN
A damage is nonrandomly distributed in the genome, i.e., ''targeted,''
at the level of individual genes. To examine this, we have been inves
tigating whether carcinogen treatment in vivo differentially alters th
e expression of specific genes. In this study, we examined the effects
of four model carcinogens that induce bulky lesions in DNA-benzo[a]py
rene (B[a]P), aflatoxin B1 (AFB1), 7,12-dimethylbenz[a]anthracene (DMB
A), and 2-acetylaminofluorene (AAF)-on the steady-state mRNA expressio
n of several constitutive and drug-inducible genes in vivo. We specifi
cally tested the hypothesis that carcinogen-induced DNA damage is pref
erentially targeted to inducible genes relative to constitutively expr
essed genes using the chick embryo as a simple in vivo test system. In
summary, the four carcinogens had no effect on the steady-state mRNA
expression of constitutively expressed beta-actin, transferrin, or alb
umin genes over a 24-h period after a single dose of each carcinogen.
In contrast, each of these same treatments significantly altered the m
RNA expression of two glutethimide-inducible genes, ALA synthase and C
YP2H1. Both the basal expression of these genes and their drug-inducib
le expression was altered. B[a]P and AFB1 had similar effects on expre
ssion of the two inducible genes and caused similar levels of covalent
adducts in total DNA, even though the administered doses differed by
30-fold. B[a]P metabolism, B[a]P binding to DNA, and the basal express
ion of CYP2H1 were similar in liver and lung. However, B[a]P significa
ntly altered basal CYP2H1 mRNA expression in liver, a tissue in which
this gene is highly inducible by glutethimide, and had no effect on ba
sal CYP2H1 mRNA expression in lung, a tissue in which this gene is not
drug-inducible. These data support the hypothesis that inducible gene
expression is a target for carcinogen-induced DNA damage in vivo. (C)
1993 Wiley-Liss, Inc.