Comparative metabolism and DNA binding of 6-nitro-5-methylchrysene and 5-methylchrysene

Gong Huey Shiue, Karam El-Bayoumy, Stephen S. Hecht

Research output: Contribution to journalArticle

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Abstract

The metabolic activation in mouse skin of the strong carcinogen, 5-methylchrysene (5-MeC) was compared to that of the inactive compound, 6-nitro-5-methylchrysene (6-NO2-5-MeC). Metabolites of 6-NO2-5-MeC, formed using rat liver homogenates, were identified based on their spectral properties and were used as markers for studies performed in vivo. In mouse epidermis in vivo, the identified metabolites of 6-NO2-5-MeC were trans-1,2-dihydro-1,2-dihydroxy-6-nitro-5-methylchrysene (6-NO2-5-MeC-1,2-diol), the precursor to a bay region dihydrodiol epoxide, trans-9,10-dihydro-9,10-dihydroxy-6-nitro-5-methylchrysene, and 6-nitro-5-hydroxymethylchrysene. The levels of 6-NO2-5-MeC-1,2-diol formed in mouse epidermis from 6-NO2-5-MeC were greater than those of the proximate carcinogen trans-1,2-dihydro-1,2-dihydroxy-5-methylchrysene (5-MeC-1,2-diol) formed from 5-MeC. The further metabolism of 6-NO25-MeC-1,2-diol was examined in mouse epidermis under conditions similar to those described previously for 5-MeC-1,2-diol. The extents of formation of 1,2,3,4-tetraols from both dihydrodiols were similar. The chromatographic patterns of DNA adducts formed in mouse epidermis from 6-NO2-5-MeC and 5-MeC were qualitatively similar; however, the extent of formation of DNA adducts from 5-MeC was 15-fold greater than from 6-NO2-5-MeC. The reactions between calf thymus DNA and the bay region 1,2-diol-3,4-epoxides of 5-MeC and 6-NO2-5-MeC were compared; the levels of adducts formed from the bay region diol epoxide of 5-MeC were about four times greater than those formed from the bay region diol epoxide of 6-NO25-MeC. The results indicate that the relatively low DNA binding in vivo of 6-NO2-5-MeC may be responsible for its apparent lack of tumorigenicity compared to 5-MeC. It is likely that nitro substitution at the 6-position of 5-MeC interferes with the structural requirements of the 1,2-diol-3,4-epoxide which are necessary for specific DNA interactions.

Original languageEnglish (US)
Pages (from-to)1327-1331
Number of pages5
JournalCarcinogenesis
Volume8
Issue number9
DOIs
StatePublished - Sep 1 1987

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DNA
Epoxy Compounds
Epidermis
DNA Adducts
6-nitro-5-methylchrysene
5-methylchrysene
Carcinogens
Skin
Liver

All Science Journal Classification (ASJC) codes

  • Cancer Research

Cite this

Shiue, Gong Huey ; El-Bayoumy, Karam ; Hecht, Stephen S. / Comparative metabolism and DNA binding of 6-nitro-5-methylchrysene and 5-methylchrysene. In: Carcinogenesis. 1987 ; Vol. 8, No. 9. pp. 1327-1331.
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title = "Comparative metabolism and DNA binding of 6-nitro-5-methylchrysene and 5-methylchrysene",
abstract = "The metabolic activation in mouse skin of the strong carcinogen, 5-methylchrysene (5-MeC) was compared to that of the inactive compound, 6-nitro-5-methylchrysene (6-NO2-5-MeC). Metabolites of 6-NO2-5-MeC, formed using rat liver homogenates, were identified based on their spectral properties and were used as markers for studies performed in vivo. In mouse epidermis in vivo, the identified metabolites of 6-NO2-5-MeC were trans-1,2-dihydro-1,2-dihydroxy-6-nitro-5-methylchrysene (6-NO2-5-MeC-1,2-diol), the precursor to a bay region dihydrodiol epoxide, trans-9,10-dihydro-9,10-dihydroxy-6-nitro-5-methylchrysene, and 6-nitro-5-hydroxymethylchrysene. The levels of 6-NO2-5-MeC-1,2-diol formed in mouse epidermis from 6-NO2-5-MeC were greater than those of the proximate carcinogen trans-1,2-dihydro-1,2-dihydroxy-5-methylchrysene (5-MeC-1,2-diol) formed from 5-MeC. The further metabolism of 6-NO25-MeC-1,2-diol was examined in mouse epidermis under conditions similar to those described previously for 5-MeC-1,2-diol. The extents of formation of 1,2,3,4-tetraols from both dihydrodiols were similar. The chromatographic patterns of DNA adducts formed in mouse epidermis from 6-NO2-5-MeC and 5-MeC were qualitatively similar; however, the extent of formation of DNA adducts from 5-MeC was 15-fold greater than from 6-NO2-5-MeC. The reactions between calf thymus DNA and the bay region 1,2-diol-3,4-epoxides of 5-MeC and 6-NO2-5-MeC were compared; the levels of adducts formed from the bay region diol epoxide of 5-MeC were about four times greater than those formed from the bay region diol epoxide of 6-NO25-MeC. The results indicate that the relatively low DNA binding in vivo of 6-NO2-5-MeC may be responsible for its apparent lack of tumorigenicity compared to 5-MeC. It is likely that nitro substitution at the 6-position of 5-MeC interferes with the structural requirements of the 1,2-diol-3,4-epoxide which are necessary for specific DNA interactions.",
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Comparative metabolism and DNA binding of 6-nitro-5-methylchrysene and 5-methylchrysene. / Shiue, Gong Huey; El-Bayoumy, Karam; Hecht, Stephen S.

In: Carcinogenesis, Vol. 8, No. 9, 01.09.1987, p. 1327-1331.

Research output: Contribution to journalArticle

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T1 - Comparative metabolism and DNA binding of 6-nitro-5-methylchrysene and 5-methylchrysene

AU - Shiue, Gong Huey

AU - El-Bayoumy, Karam

AU - Hecht, Stephen S.

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N2 - The metabolic activation in mouse skin of the strong carcinogen, 5-methylchrysene (5-MeC) was compared to that of the inactive compound, 6-nitro-5-methylchrysene (6-NO2-5-MeC). Metabolites of 6-NO2-5-MeC, formed using rat liver homogenates, were identified based on their spectral properties and were used as markers for studies performed in vivo. In mouse epidermis in vivo, the identified metabolites of 6-NO2-5-MeC were trans-1,2-dihydro-1,2-dihydroxy-6-nitro-5-methylchrysene (6-NO2-5-MeC-1,2-diol), the precursor to a bay region dihydrodiol epoxide, trans-9,10-dihydro-9,10-dihydroxy-6-nitro-5-methylchrysene, and 6-nitro-5-hydroxymethylchrysene. The levels of 6-NO2-5-MeC-1,2-diol formed in mouse epidermis from 6-NO2-5-MeC were greater than those of the proximate carcinogen trans-1,2-dihydro-1,2-dihydroxy-5-methylchrysene (5-MeC-1,2-diol) formed from 5-MeC. The further metabolism of 6-NO25-MeC-1,2-diol was examined in mouse epidermis under conditions similar to those described previously for 5-MeC-1,2-diol. The extents of formation of 1,2,3,4-tetraols from both dihydrodiols were similar. The chromatographic patterns of DNA adducts formed in mouse epidermis from 6-NO2-5-MeC and 5-MeC were qualitatively similar; however, the extent of formation of DNA adducts from 5-MeC was 15-fold greater than from 6-NO2-5-MeC. The reactions between calf thymus DNA and the bay region 1,2-diol-3,4-epoxides of 5-MeC and 6-NO2-5-MeC were compared; the levels of adducts formed from the bay region diol epoxide of 5-MeC were about four times greater than those formed from the bay region diol epoxide of 6-NO25-MeC. The results indicate that the relatively low DNA binding in vivo of 6-NO2-5-MeC may be responsible for its apparent lack of tumorigenicity compared to 5-MeC. It is likely that nitro substitution at the 6-position of 5-MeC interferes with the structural requirements of the 1,2-diol-3,4-epoxide which are necessary for specific DNA interactions.

AB - The metabolic activation in mouse skin of the strong carcinogen, 5-methylchrysene (5-MeC) was compared to that of the inactive compound, 6-nitro-5-methylchrysene (6-NO2-5-MeC). Metabolites of 6-NO2-5-MeC, formed using rat liver homogenates, were identified based on their spectral properties and were used as markers for studies performed in vivo. In mouse epidermis in vivo, the identified metabolites of 6-NO2-5-MeC were trans-1,2-dihydro-1,2-dihydroxy-6-nitro-5-methylchrysene (6-NO2-5-MeC-1,2-diol), the precursor to a bay region dihydrodiol epoxide, trans-9,10-dihydro-9,10-dihydroxy-6-nitro-5-methylchrysene, and 6-nitro-5-hydroxymethylchrysene. The levels of 6-NO2-5-MeC-1,2-diol formed in mouse epidermis from 6-NO2-5-MeC were greater than those of the proximate carcinogen trans-1,2-dihydro-1,2-dihydroxy-5-methylchrysene (5-MeC-1,2-diol) formed from 5-MeC. The further metabolism of 6-NO25-MeC-1,2-diol was examined in mouse epidermis under conditions similar to those described previously for 5-MeC-1,2-diol. The extents of formation of 1,2,3,4-tetraols from both dihydrodiols were similar. The chromatographic patterns of DNA adducts formed in mouse epidermis from 6-NO2-5-MeC and 5-MeC were qualitatively similar; however, the extent of formation of DNA adducts from 5-MeC was 15-fold greater than from 6-NO2-5-MeC. The reactions between calf thymus DNA and the bay region 1,2-diol-3,4-epoxides of 5-MeC and 6-NO2-5-MeC were compared; the levels of adducts formed from the bay region diol epoxide of 5-MeC were about four times greater than those formed from the bay region diol epoxide of 6-NO25-MeC. The results indicate that the relatively low DNA binding in vivo of 6-NO2-5-MeC may be responsible for its apparent lack of tumorigenicity compared to 5-MeC. It is likely that nitro substitution at the 6-position of 5-MeC interferes with the structural requirements of the 1,2-diol-3,4-epoxide which are necessary for specific DNA interactions.

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