Preferential alteration of inducible gene expression in vivo by carcinogens that induce bulky DNA lesions.
Our laboratory is interested in whether chemical carcinogen-induced DNA damage is nonrandomly distributed in the genome, i.e., "targeted," at the level of individual genes. To examine this, we have been investigating whether carcinogen treatment in vivo differentially alters the expression of specific genes. In this study, we examined the effects of four model carcinogens that induce bulky lesions in DNA--benzo[a]pyrene (B[a]P), aflatoxin B1 (AFB1), 7,12-dimethylbenz[a]anthracene (DMBA), and 2-acetylaminofluorene (AAF)--on the steady-state mRNA expression of several constitutive and drug-inducible genes in vivo. We specifically tested the hypothesis that carcinogen-induced DNA damage is preferentially targeted to inducible genes relative to constitutively expressed 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 albumin genes over a 24-h period after a single dose of each carcinogen. In contrast, each of these same treatments significantly altered the mRNA expression of two glutethimide-inducible genes, ALA synthase and CYP2H1. Both the basal expression of these genes and their drug-inducible expression was altered. B[a]P and AFB1 had similar effects on expression 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 binding to DNA, and the basal expression of CYP2H1 were similar in liver and lung. However, B[a]P significantly altered basal CYP2H1 mRNA expression in liver, a tissue in which this gene is highly inducible by glutethimide, and had no effect on basal 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.
Hamilton
J W
JW
Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH 03755-3835.
Louis
C A
CA
Doherty
K A
KA
Hunt
S R
SR
Reed
M J
MJ
Treadwell
M D
MD
D000624:5-Aminolevulinate Synthetase / Q000235:genetics; D000199:Actins / Q000235:genetics; D000418:Albumins / Q000235:genetics; D000818:Animals; D001564:Benzo(a)pyrene / Q000378:metabolism / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity*; D002642:Chick Embryo; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D005984:Glutethimide / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D012680:Sensitivity and Specificity; D014168:Transferrin / Q000235:genetics
D000199:Actins; D000418:Albumins; D002273:Carcinogens; D012333:RNA, Messenger; D014168:Transferrin; D001564:Benzo(a)pyrene; D012313:RNA; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D005984:Glutethimide; D000624:5-Aminolevulinate Synthetase