TY - JOUR
T1 - DNA adducts of heterocyclic amines
T2 - Formation, removal and inhibition by dietary components
AU - Schut, Herman A.J.
AU - Cummings, David A.
AU - Smale, Maarten H.E.
AU - Josyula, Shylaja
AU - Friesen, Marlin D.
N1 - Funding Information:
These studies were supported in part by grants from the National Institutes of Health (CA47484) and the National Live Stock and Meat Board. Lisa Twining and Kim Earle provided able technical assistance.
PY - 1997/5/12
Y1 - 1997/5/12
N2 - The dietary mutagens 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are carcinogenic in rodents. In F344 rats PhIP induces mammary tumors in females and colon tumors in males, while IQ induces tumors principally in the liver, Zymbal gland and intestines. In CDF1 mice, IQ induces liver, lung and forestomach tumors. We have evaluated the dynamics of formation, removal and inhibition of PhIP- and IQ-DNA adducts in these rodents. After bolus doses (50 mg/kg, by gavage) of IQ or PhIP, both IQ- and PhIP-DNA adducts were removed rapidly from both target and nontarget organs, while after 3-4 weeks of feeding IQ or PhIP (0.01-0.04%) adduct removal was much slower. Gavaging of male F344 rats with PhIP (0.1-1000 μg/kg/day) for 23 days resulted in accumulation of PhIP-DNA adducts in various organs, but adducts were detectable only at 100 or 1000 μg/kg/day. Urinary excretion of unchanged PhIP was a constant proportion (1.6-2.1%) of the daily dose over the entire dose range and was independent of duration of exposure. When weanling female F344 rats were exposed to dietary PhIP (0.01-0.04%) for 1-4 weeks, the presence of either conjugated linoleic acid (CLA; 0.1-1.0%) or indole-3-carbinol (I3C; 0.1%) in the diet inhibited PhIP-DNA adduct formation (58-99%) in various organs, including the mammary gland and the colon. Similarly, the inclusion of 0.075% 4-ipomeanol (IPO) in the diet of male CDF1 mice exposed for 3 weeks to dietary IQ (0.01%) resulted in inhibition of IQ-DNA adduct formation (30-59%) in the target organs (liver, lungs, stomach) but not in a number of other organs. It is concluded that (1) the rate of PhLP- and IQ-DNA adduct removal depends on the dose and frequency of administration, (2) urinary PhIP may be a good biomarker of recent PhIP exposure and (3) CLA, 13C and IPO are potential chemopreventive agents against PhIP- or IQ-induced tumors in rodents.
AB - The dietary mutagens 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are carcinogenic in rodents. In F344 rats PhIP induces mammary tumors in females and colon tumors in males, while IQ induces tumors principally in the liver, Zymbal gland and intestines. In CDF1 mice, IQ induces liver, lung and forestomach tumors. We have evaluated the dynamics of formation, removal and inhibition of PhIP- and IQ-DNA adducts in these rodents. After bolus doses (50 mg/kg, by gavage) of IQ or PhIP, both IQ- and PhIP-DNA adducts were removed rapidly from both target and nontarget organs, while after 3-4 weeks of feeding IQ or PhIP (0.01-0.04%) adduct removal was much slower. Gavaging of male F344 rats with PhIP (0.1-1000 μg/kg/day) for 23 days resulted in accumulation of PhIP-DNA adducts in various organs, but adducts were detectable only at 100 or 1000 μg/kg/day. Urinary excretion of unchanged PhIP was a constant proportion (1.6-2.1%) of the daily dose over the entire dose range and was independent of duration of exposure. When weanling female F344 rats were exposed to dietary PhIP (0.01-0.04%) for 1-4 weeks, the presence of either conjugated linoleic acid (CLA; 0.1-1.0%) or indole-3-carbinol (I3C; 0.1%) in the diet inhibited PhIP-DNA adduct formation (58-99%) in various organs, including the mammary gland and the colon. Similarly, the inclusion of 0.075% 4-ipomeanol (IPO) in the diet of male CDF1 mice exposed for 3 weeks to dietary IQ (0.01%) resulted in inhibition of IQ-DNA adduct formation (30-59%) in the target organs (liver, lungs, stomach) but not in a number of other organs. It is concluded that (1) the rate of PhLP- and IQ-DNA adduct removal depends on the dose and frequency of administration, (2) urinary PhIP may be a good biomarker of recent PhIP exposure and (3) CLA, 13C and IPO are potential chemopreventive agents against PhIP- or IQ-induced tumors in rodents.
KW - Chemoprevention
KW - DNA adduct
KW - Food mutagen
KW - Heterocyclic amine
KW - IQ
KW - PhIP
UR - http://www.scopus.com/inward/record.url?scp=0030915037&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0030915037&partnerID=8YFLogxK
U2 - 10.1016/S0027-5107(97)00042-0
DO - 10.1016/S0027-5107(97)00042-0
M3 - Article
C2 - 9202755
AN - SCOPUS:0030915037
SN - 0027-5107
VL - 376
SP - 185
EP - 194
JO - Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
JF - Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
IS - 1-2
ER -