Comparative DNA binding of polynuclear aromatic hydrocarbons and their dihydrodiol and bay region diolepoxide metabolites in newborn mouse lung and liver

Assieh A. Melikian, Kulkarni A. Prahalad, Shantu Amin, Stephen S. Hecht

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Abstract

Bay region diolepoxides of polynuclear aromatic hydrocarbons (PAHs) generally are more tumorigenic than their parent PAHs in newborn mice. This contrasts to the results obtained in mouse skin, in which the same diolepoxides are frequently less tumorigenic than their parents. In order to evaluate mechanism(s) responsible for this behavior we have investigated the binding of metabolites of [3H]benzo[a]pyrene (B[a]P), [3H]5- and [3H]6-methylchrysene (5-MeC and 6-MeC) and their corresponding dihydradiols and bay region diolepoxides to pulmonary and hepatic DNA in male and female newborn mice and compared the results with their tumorigenic activities. Groups of 1 day old mice were treated with 0.4 or 4 nmol of the appropriate compounds in DMSO by i.p. injection. HPLC analysis of DNA hydrolysates obtained 24 h after treatment indicated that levels of diolepoxide-DNA adducts following treatment with (±)-[3H]7,8-dihydroxy-7,8-dihydroB[a]P and (±)-[3]anti-7,8-dihydroxy-9,10-epoxy-7,8,9,l0-tetrah hyroB[a]P are 5- and 10-fold higher than those formed from P [3H]B[a]P. The major products (70-80%) released upon enzymatic hydrolysis of DNA following treatment with [3H]B[a]P, [3H]5-MeC and [3H]6-MeC were unidentified polar compounds. Levels of these unknown products were lower and formation of diolepoxide-DNA adducts higher when test compounds were changed from parent PAHs to the corresponding dihydrodiols and diolepoxides. Comparison of these results with those of tumorigenesis studies indicates a correlation between formation of B[a]P-diolepoxide-DNA adducts and induction of tumors in newborn mouse lung, but not in liver. These observations are consistent with the high sensitivity of the newborn mouse lung towards the turmorigenic effects of bay region diolepoxides. Previous studies have demonstrated that 1R,2S-dihydroxy-3S,4R,epoxy, 1,2,3,4-tetrahydro-5-MeC (5-MeC-lR,2S-diol-3S,4R-epoxide) is a potent lung tumorigen while the corresponding diol-epoxide of 6-MeC had no effect in newborn mice. From the results of the present study, we estimate that at equimolar doses the formation of diolepoxide-DNA asdducts from 5-MeC-lR,2S-diol-3S,4R-epoxide would be at least 20-fold greater than from the corresponding diolepoxide of 6-MeC in newborn mouse lung. Thus, the higher tumorigenic activity of 5-MeC-1R,2S-diol-3S,4R-epoxide compared to that of the corrrsponding diol epoxide of 6-MeC is partially due to its greater extent of DNA damage.

Original languageEnglish (US)
Pages (from-to)1665-1670
Number of pages6
JournalCarcinogenesis
Volume12
Issue number9
DOIs
StatePublished - Sep 1 1991

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Polycyclic Aromatic Hydrocarbons
Epoxy Compounds
Lung
Liver
DNA
DNA Adducts
Benzo(a)pyrene
trans-1,2-dihydro-1,2-naphthalenediol
Dimethyl Sulfoxide
DNA Damage
Carcinogenesis
Hydrolysis
Therapeutics
High Pressure Liquid Chromatography
Skin
Injections

All Science Journal Classification (ASJC) codes

  • Cancer Research

Cite this

@article{3e32f9887efa4d4fa23fd0ed3b0f8750,
title = "Comparative DNA binding of polynuclear aromatic hydrocarbons and their dihydrodiol and bay region diolepoxide metabolites in newborn mouse lung and liver",
abstract = "Bay region diolepoxides of polynuclear aromatic hydrocarbons (PAHs) generally are more tumorigenic than their parent PAHs in newborn mice. This contrasts to the results obtained in mouse skin, in which the same diolepoxides are frequently less tumorigenic than their parents. In order to evaluate mechanism(s) responsible for this behavior we have investigated the binding of metabolites of [3H]benzo[a]pyrene (B[a]P), [3H]5- and [3H]6-methylchrysene (5-MeC and 6-MeC) and their corresponding dihydradiols and bay region diolepoxides to pulmonary and hepatic DNA in male and female newborn mice and compared the results with their tumorigenic activities. Groups of 1 day old mice were treated with 0.4 or 4 nmol of the appropriate compounds in DMSO by i.p. injection. HPLC analysis of DNA hydrolysates obtained 24 h after treatment indicated that levels of diolepoxide-DNA adducts following treatment with (±)-[3H]7,8-dihydroxy-7,8-dihydroB[a]P and (±)-[3]anti-7,8-dihydroxy-9,10-epoxy-7,8,9,l0-tetrah hyroB[a]P are 5- and 10-fold higher than those formed from P [3H]B[a]P. The major products (70-80{\%}) released upon enzymatic hydrolysis of DNA following treatment with [3H]B[a]P, [3H]5-MeC and [3H]6-MeC were unidentified polar compounds. Levels of these unknown products were lower and formation of diolepoxide-DNA adducts higher when test compounds were changed from parent PAHs to the corresponding dihydrodiols and diolepoxides. Comparison of these results with those of tumorigenesis studies indicates a correlation between formation of B[a]P-diolepoxide-DNA adducts and induction of tumors in newborn mouse lung, but not in liver. These observations are consistent with the high sensitivity of the newborn mouse lung towards the turmorigenic effects of bay region diolepoxides. Previous studies have demonstrated that 1R,2S-dihydroxy-3S,4R,epoxy, 1,2,3,4-tetrahydro-5-MeC (5-MeC-lR,2S-diol-3S,4R-epoxide) is a potent lung tumorigen while the corresponding diol-epoxide of 6-MeC had no effect in newborn mice. From the results of the present study, we estimate that at equimolar doses the formation of diolepoxide-DNA asdducts from 5-MeC-lR,2S-diol-3S,4R-epoxide would be at least 20-fold greater than from the corresponding diolepoxide of 6-MeC in newborn mouse lung. Thus, the higher tumorigenic activity of 5-MeC-1R,2S-diol-3S,4R-epoxide compared to that of the corrrsponding diol epoxide of 6-MeC is partially due to its greater extent of DNA damage.",
author = "Melikian, {Assieh A.} and Prahalad, {Kulkarni A.} and Shantu Amin and Hecht, {Stephen S.}",
year = "1991",
month = "9",
day = "1",
doi = "10.1093/carcin/12.9.1665",
language = "English (US)",
volume = "12",
pages = "1665--1670",
journal = "Carcinogenesis",
issn = "0143-3334",
publisher = "Oxford University Press",
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}

Comparative DNA binding of polynuclear aromatic hydrocarbons and their dihydrodiol and bay region diolepoxide metabolites in newborn mouse lung and liver. / Melikian, Assieh A.; Prahalad, Kulkarni A.; Amin, Shantu; Hecht, Stephen S.

In: Carcinogenesis, Vol. 12, No. 9, 01.09.1991, p. 1665-1670.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Comparative DNA binding of polynuclear aromatic hydrocarbons and their dihydrodiol and bay region diolepoxide metabolites in newborn mouse lung and liver

AU - Melikian, Assieh A.

AU - Prahalad, Kulkarni A.

AU - Amin, Shantu

AU - Hecht, Stephen S.

PY - 1991/9/1

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N2 - Bay region diolepoxides of polynuclear aromatic hydrocarbons (PAHs) generally are more tumorigenic than their parent PAHs in newborn mice. This contrasts to the results obtained in mouse skin, in which the same diolepoxides are frequently less tumorigenic than their parents. In order to evaluate mechanism(s) responsible for this behavior we have investigated the binding of metabolites of [3H]benzo[a]pyrene (B[a]P), [3H]5- and [3H]6-methylchrysene (5-MeC and 6-MeC) and their corresponding dihydradiols and bay region diolepoxides to pulmonary and hepatic DNA in male and female newborn mice and compared the results with their tumorigenic activities. Groups of 1 day old mice were treated with 0.4 or 4 nmol of the appropriate compounds in DMSO by i.p. injection. HPLC analysis of DNA hydrolysates obtained 24 h after treatment indicated that levels of diolepoxide-DNA adducts following treatment with (±)-[3H]7,8-dihydroxy-7,8-dihydroB[a]P and (±)-[3]anti-7,8-dihydroxy-9,10-epoxy-7,8,9,l0-tetrah hyroB[a]P are 5- and 10-fold higher than those formed from P [3H]B[a]P. The major products (70-80%) released upon enzymatic hydrolysis of DNA following treatment with [3H]B[a]P, [3H]5-MeC and [3H]6-MeC were unidentified polar compounds. Levels of these unknown products were lower and formation of diolepoxide-DNA adducts higher when test compounds were changed from parent PAHs to the corresponding dihydrodiols and diolepoxides. Comparison of these results with those of tumorigenesis studies indicates a correlation between formation of B[a]P-diolepoxide-DNA adducts and induction of tumors in newborn mouse lung, but not in liver. These observations are consistent with the high sensitivity of the newborn mouse lung towards the turmorigenic effects of bay region diolepoxides. Previous studies have demonstrated that 1R,2S-dihydroxy-3S,4R,epoxy, 1,2,3,4-tetrahydro-5-MeC (5-MeC-lR,2S-diol-3S,4R-epoxide) is a potent lung tumorigen while the corresponding diol-epoxide of 6-MeC had no effect in newborn mice. From the results of the present study, we estimate that at equimolar doses the formation of diolepoxide-DNA asdducts from 5-MeC-lR,2S-diol-3S,4R-epoxide would be at least 20-fold greater than from the corresponding diolepoxide of 6-MeC in newborn mouse lung. Thus, the higher tumorigenic activity of 5-MeC-1R,2S-diol-3S,4R-epoxide compared to that of the corrrsponding diol epoxide of 6-MeC is partially due to its greater extent of DNA damage.

AB - Bay region diolepoxides of polynuclear aromatic hydrocarbons (PAHs) generally are more tumorigenic than their parent PAHs in newborn mice. This contrasts to the results obtained in mouse skin, in which the same diolepoxides are frequently less tumorigenic than their parents. In order to evaluate mechanism(s) responsible for this behavior we have investigated the binding of metabolites of [3H]benzo[a]pyrene (B[a]P), [3H]5- and [3H]6-methylchrysene (5-MeC and 6-MeC) and their corresponding dihydradiols and bay region diolepoxides to pulmonary and hepatic DNA in male and female newborn mice and compared the results with their tumorigenic activities. Groups of 1 day old mice were treated with 0.4 or 4 nmol of the appropriate compounds in DMSO by i.p. injection. HPLC analysis of DNA hydrolysates obtained 24 h after treatment indicated that levels of diolepoxide-DNA adducts following treatment with (±)-[3H]7,8-dihydroxy-7,8-dihydroB[a]P and (±)-[3]anti-7,8-dihydroxy-9,10-epoxy-7,8,9,l0-tetrah hyroB[a]P are 5- and 10-fold higher than those formed from P [3H]B[a]P. The major products (70-80%) released upon enzymatic hydrolysis of DNA following treatment with [3H]B[a]P, [3H]5-MeC and [3H]6-MeC were unidentified polar compounds. Levels of these unknown products were lower and formation of diolepoxide-DNA adducts higher when test compounds were changed from parent PAHs to the corresponding dihydrodiols and diolepoxides. Comparison of these results with those of tumorigenesis studies indicates a correlation between formation of B[a]P-diolepoxide-DNA adducts and induction of tumors in newborn mouse lung, but not in liver. These observations are consistent with the high sensitivity of the newborn mouse lung towards the turmorigenic effects of bay region diolepoxides. Previous studies have demonstrated that 1R,2S-dihydroxy-3S,4R,epoxy, 1,2,3,4-tetrahydro-5-MeC (5-MeC-lR,2S-diol-3S,4R-epoxide) is a potent lung tumorigen while the corresponding diol-epoxide of 6-MeC had no effect in newborn mice. From the results of the present study, we estimate that at equimolar doses the formation of diolepoxide-DNA asdducts from 5-MeC-lR,2S-diol-3S,4R-epoxide would be at least 20-fold greater than from the corresponding diolepoxide of 6-MeC in newborn mouse lung. Thus, the higher tumorigenic activity of 5-MeC-1R,2S-diol-3S,4R-epoxide compared to that of the corrrsponding diol epoxide of 6-MeC is partially due to its greater extent of DNA damage.

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