Formation and persistence of DNA adducts of 2-amino-3-methylimidazo[4,5-f]quinoline in the rat and nonhuman primates

Robert J. Turesky; Rafael Munoz Box; Jovanka Markovic; Eric Gremaud; Elizabeth G. Snyderwine

doi:10.1016/S0027-5107(97)00048-1

Formation and persistence of DNA adducts of 2-amino-3-methylimidazo[4,5-f]quinoline in the rat and nonhuman primates

Robert J. Turesky, Rafael Munoz Box, Jovanka Markovic, Eric Gremaud, Elizabeth G. Snyderwine

Medicinal Chemistry

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Abstract

The formation and persistence of the two principal DNA adducts of the food derived carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) have been investigated in rats and nonhuman primates. DNA adduct formation in the liver of male Fischer-344 rats occurred in a dose-dependent manner (0.01-20 mg/kg) where N-(deoxyguanosin-8-yl)-2-amino-3 -methylimidazo[4,5-f]quinoline (dG-C8-IQ) and 5-(deoxyguanosin-N²-yl)-2-amino-3-methylimidazo[4,5-f]quinoline (dG-N²-IQ) accounted for approximately 60-80% and 20-40%, respectively, of the total adducts observed by ³²P postlabeling. Similar DNA adduct profiles were observed in kidney and colorectal tissue of rats given a single oral dose of IQ (20 mg/kg) which, when given chronically to this species, results in tumorigenesis in liver and colorectum, but not in kidney. dG-C8-IQ was removed more rapidly than dG-N²-IQ from liver and kidney, but removal of both adducts from the colorectum closely followed cell replication, Similar DNA adduct profiles were observed in liver and extrahepatic tissues of nonhuman primates following a single dose of IQ (20 mg/kg). In chronically treated monkeys undergoing carcinogen bioassay, there was a sharp increase in the contribution of dG-N²-IQ to total DNA adducts in all slowly dividing tissues. There was no preferential accumulation of dG-N²-IQ in the colon, a tissue with a high rate of cell division, and dG-C8-IQ remained the predominant lesion, These findings point to a preferential removal of the dG-C8-IQ adduct by enzyme repair system(s) in slowly dividing tissues in both rats and nonhuman primates.

Original language	English (US)
Pages (from-to)	235-241
Number of pages	7
Journal	Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
Volume	376
Issue number	1-2
DOIs	https://doi.org/10.1016/S0027-5107(97)00048-1
State	Published - May 12 1997

Bibliographical note

Funding Information:
The authors thank Drs. Unnur P. Thorgeirsson and Richard H. Adamson (National Cancer Institute) for personal communications and help with receiving the monkey autopsies; Dr. Dan Dalgard and Mrs. Jeannette Reeves (Corning-Hazleton) for assistance with the monkey colony; and Dr. Snorri S. Thorgeirsson (National Cancer Institute) for support and helpful discussions. Financial support for the chronic monkey dosing was provided, in part, by a Grant-in-Aid from the Ministry of Health and Welfare for a comprehensive 10-year strategy for cancer control, Japan.

Keywords

Adduct persistence and removal
DNA adduct formation
Food carcinogen

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Formation and persistence of DNA adducts of 2-amino-3-methylimidazo[4,5-f]quinoline in the rat and nonhuman primates. / Turesky, Robert J.; Box, Rafael Munoz; Markovic, Jovanka et al.
In: Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis, Vol. 376, No. 1-2, 12.05.1997, p. 235-241.

Research output: Contribution to journal › Article › peer-review

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abstract = "The formation and persistence of the two principal DNA adducts of the food derived carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) have been investigated in rats and nonhuman primates. DNA adduct formation in the liver of male Fischer-344 rats occurred in a dose-dependent manner (0.01-20 mg/kg) where N-(deoxyguanosin-8-yl)-2-amino-3 -methylimidazo[4,5-f]quinoline (dG-C8-IQ) and 5-(deoxyguanosin-N2-yl)-2-amino-3-methylimidazo[4,5-f]quinoline (dG-N2-IQ) accounted for approximately 60-80% and 20-40%, respectively, of the total adducts observed by 32P postlabeling. Similar DNA adduct profiles were observed in kidney and colorectal tissue of rats given a single oral dose of IQ (20 mg/kg) which, when given chronically to this species, results in tumorigenesis in liver and colorectum, but not in kidney. dG-C8-IQ was removed more rapidly than dG-N2-IQ from liver and kidney, but removal of both adducts from the colorectum closely followed cell replication, Similar DNA adduct profiles were observed in liver and extrahepatic tissues of nonhuman primates following a single dose of IQ (20 mg/kg). In chronically treated monkeys undergoing carcinogen bioassay, there was a sharp increase in the contribution of dG-N2-IQ to total DNA adducts in all slowly dividing tissues. There was no preferential accumulation of dG-N2-IQ in the colon, a tissue with a high rate of cell division, and dG-C8-IQ remained the predominant lesion, These findings point to a preferential removal of the dG-C8-IQ adduct by enzyme repair system(s) in slowly dividing tissues in both rats and nonhuman primates.",

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Formation and persistence of DNA adducts of 2-amino-3-methylimidazo[4,5-f]quinoline in the rat and nonhuman primates

Abstract

Bibliographical note

Keywords

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