TY - JOUR
T1 - Preferential alteration of inducible gene expression in vivo by carcinogens that induce bulky DNA lesions
AU - Hamilton, Joshua W.
AU - Louis, Claudine A.
AU - Doherty, Kristen A.
AU - Hunt, Steven R.
AU - Reed, Michael J.
AU - Treadwell, Melinda D.
PY - 1993
Y1 - 1993
N2 - 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 β‐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 metabolism, 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. © 1993 Wiley‐Liss, Inc.
AB - 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 β‐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 metabolism, 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. © 1993 Wiley‐Liss, Inc.
KW - 2‐acetylaminofluorene
KW - 7,12‐dimethylbenz[a]anthracene
KW - DNA damage
KW - aflatoxin B
KW - benzo[a]pyrene
UR - http://www.scopus.com/inward/record.url?scp=0027164445&partnerID=8YFLogxK
U2 - 10.1002/mc.2940080109
DO - 10.1002/mc.2940080109
M3 - Article
C2 - 7688968
AN - SCOPUS:0027164445
SN - 0899-1987
VL - 8
SP - 34
EP - 43
JO - Molecular Carcinogenesis
JF - Molecular Carcinogenesis
IS - 1
ER -