PREFERENTIAL ALTERATION OF INDUCIBLE GENE-EXPRESSION IN-VIVO BY CARCINOGENS THAT INDUCE BULKY DNA LESIONS

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.