Effects of fluorine substitution on the tumor initiating activity and metabolism of 5-hydroxymethylchrysene, a tumorigenic metabolite of 5-methylchrysene

Shantu Amin, Amy Juchatz, Keizo Furuya, Stephen S. Hecht

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Abstract

The tumor initiating activity on mouse skin of 5-hydroxymethylchrysene (5-HOMeC), a major metabolite of the carcinogen, 5-methylchrysene (5-MeC), was investigated. After an initiating dose of 30 μg, with promotion by tetradecanoylphorbol acetate, 5-HOMeC induced skin tumors in 90% of the animals, with 9.5 tumors/mouse. 5-MeC gave a 75% incidence of skin tumors with 6.2 tumors/mouse. The tumorigenic activities after a 10μg initiating dose were: 5-HOMeC, 45% skin tumor-bearing animals and 2.6 tumors/-mouse; 5-MeC, 55% skin tumor-bearing animals and 5.6 tumors/mouse. In contrast, 6-hydroxymethylchrysene was inactive. To investigate the mechanism of activation of 5-HOMeC, 3-fluoro-5-hydroxymethylchrysene (3-F-5-HOMeC) and 7-fluoro-5-hydroxymethylchrysene (7-F-5-HOMeC) were prepared and assayed for tumor initiating activity at a dose of 30 μg. (7-F-5-HOMeC) gave 95% tumor-bearing animals and 7.9 tumors/animal whereas 3-F-5-HOMeC gave only 5% tumor-bearing animals and 0.1 s/animal. The inhibition of tumorigenicity by substitution of fluorine at the 3-position, but not the 7-position of 5-HOMeC is strictly analogous to results obtained previously with 5-MeC and suggests a similar mechanism of activation for both compounds. The metabolites formed upon incubation of 5-HOMeC with cofactors and the 9000 × g supernatant from Aroclor pretreated rats were separated by h.p.l.c. The 1,2-dihydrodiol and 7,8-dihydrodiol of 5-HOMeC were identified. The major phenolic metabolite was identified as 1-hydroxy-5-hydroxymethylchrysene. In the in vitro metabolism of 7-F-5-HOMeC under the same conditions, we identified the 1,2-dihydrodiol but not the 7,8-dihydrodiol. In the metabolism of 3-F-5-HOMeC, oxidation in the 1-4 ring was inhibited relative to that observed in the metabolism of 5-HOMeC. These results suggest that 5-HOMeC is activated primarily through formation of its 1,2-dihydrodiol.

Original languageEnglish (US)
Pages (from-to)1027-1032
Number of pages6
JournalCarcinogenesis
Volume2
Issue number10
DOIs
StatePublished - Dec 1 1981

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Fluorine
Neoplasms
Skin
5-hydroxymethylchrysene
5-methylchrysene
Aroclors
Tetradecanoylphorbol Acetate

All Science Journal Classification (ASJC) codes

  • Cancer Research

Cite this

@article{e64ac6409b4b4aba887bba6bc9ee84ff,
title = "Effects of fluorine substitution on the tumor initiating activity and metabolism of 5-hydroxymethylchrysene, a tumorigenic metabolite of 5-methylchrysene",
abstract = "The tumor initiating activity on mouse skin of 5-hydroxymethylchrysene (5-HOMeC), a major metabolite of the carcinogen, 5-methylchrysene (5-MeC), was investigated. After an initiating dose of 30 μg, with promotion by tetradecanoylphorbol acetate, 5-HOMeC induced skin tumors in 90{\%} of the animals, with 9.5 tumors/mouse. 5-MeC gave a 75{\%} incidence of skin tumors with 6.2 tumors/mouse. The tumorigenic activities after a 10μg initiating dose were: 5-HOMeC, 45{\%} skin tumor-bearing animals and 2.6 tumors/-mouse; 5-MeC, 55{\%} skin tumor-bearing animals and 5.6 tumors/mouse. In contrast, 6-hydroxymethylchrysene was inactive. To investigate the mechanism of activation of 5-HOMeC, 3-fluoro-5-hydroxymethylchrysene (3-F-5-HOMeC) and 7-fluoro-5-hydroxymethylchrysene (7-F-5-HOMeC) were prepared and assayed for tumor initiating activity at a dose of 30 μg. (7-F-5-HOMeC) gave 95{\%} tumor-bearing animals and 7.9 tumors/animal whereas 3-F-5-HOMeC gave only 5{\%} tumor-bearing animals and 0.1 s/animal. The inhibition of tumorigenicity by substitution of fluorine at the 3-position, but not the 7-position of 5-HOMeC is strictly analogous to results obtained previously with 5-MeC and suggests a similar mechanism of activation for both compounds. The metabolites formed upon incubation of 5-HOMeC with cofactors and the 9000 × g supernatant from Aroclor pretreated rats were separated by h.p.l.c. The 1,2-dihydrodiol and 7,8-dihydrodiol of 5-HOMeC were identified. The major phenolic metabolite was identified as 1-hydroxy-5-hydroxymethylchrysene. In the in vitro metabolism of 7-F-5-HOMeC under the same conditions, we identified the 1,2-dihydrodiol but not the 7,8-dihydrodiol. In the metabolism of 3-F-5-HOMeC, oxidation in the 1-4 ring was inhibited relative to that observed in the metabolism of 5-HOMeC. These results suggest that 5-HOMeC is activated primarily through formation of its 1,2-dihydrodiol.",
author = "Shantu Amin and Amy Juchatz and Keizo Furuya and Hecht, {Stephen S.}",
year = "1981",
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language = "English (US)",
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Effects of fluorine substitution on the tumor initiating activity and metabolism of 5-hydroxymethylchrysene, a tumorigenic metabolite of 5-methylchrysene. / Amin, Shantu; Juchatz, Amy; Furuya, Keizo; Hecht, Stephen S.

In: Carcinogenesis, Vol. 2, No. 10, 01.12.1981, p. 1027-1032.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Effects of fluorine substitution on the tumor initiating activity and metabolism of 5-hydroxymethylchrysene, a tumorigenic metabolite of 5-methylchrysene

AU - Amin, Shantu

AU - Juchatz, Amy

AU - Furuya, Keizo

AU - Hecht, Stephen S.

PY - 1981/12/1

Y1 - 1981/12/1

N2 - The tumor initiating activity on mouse skin of 5-hydroxymethylchrysene (5-HOMeC), a major metabolite of the carcinogen, 5-methylchrysene (5-MeC), was investigated. After an initiating dose of 30 μg, with promotion by tetradecanoylphorbol acetate, 5-HOMeC induced skin tumors in 90% of the animals, with 9.5 tumors/mouse. 5-MeC gave a 75% incidence of skin tumors with 6.2 tumors/mouse. The tumorigenic activities after a 10μg initiating dose were: 5-HOMeC, 45% skin tumor-bearing animals and 2.6 tumors/-mouse; 5-MeC, 55% skin tumor-bearing animals and 5.6 tumors/mouse. In contrast, 6-hydroxymethylchrysene was inactive. To investigate the mechanism of activation of 5-HOMeC, 3-fluoro-5-hydroxymethylchrysene (3-F-5-HOMeC) and 7-fluoro-5-hydroxymethylchrysene (7-F-5-HOMeC) were prepared and assayed for tumor initiating activity at a dose of 30 μg. (7-F-5-HOMeC) gave 95% tumor-bearing animals and 7.9 tumors/animal whereas 3-F-5-HOMeC gave only 5% tumor-bearing animals and 0.1 s/animal. The inhibition of tumorigenicity by substitution of fluorine at the 3-position, but not the 7-position of 5-HOMeC is strictly analogous to results obtained previously with 5-MeC and suggests a similar mechanism of activation for both compounds. The metabolites formed upon incubation of 5-HOMeC with cofactors and the 9000 × g supernatant from Aroclor pretreated rats were separated by h.p.l.c. The 1,2-dihydrodiol and 7,8-dihydrodiol of 5-HOMeC were identified. The major phenolic metabolite was identified as 1-hydroxy-5-hydroxymethylchrysene. In the in vitro metabolism of 7-F-5-HOMeC under the same conditions, we identified the 1,2-dihydrodiol but not the 7,8-dihydrodiol. In the metabolism of 3-F-5-HOMeC, oxidation in the 1-4 ring was inhibited relative to that observed in the metabolism of 5-HOMeC. These results suggest that 5-HOMeC is activated primarily through formation of its 1,2-dihydrodiol.

AB - The tumor initiating activity on mouse skin of 5-hydroxymethylchrysene (5-HOMeC), a major metabolite of the carcinogen, 5-methylchrysene (5-MeC), was investigated. After an initiating dose of 30 μg, with promotion by tetradecanoylphorbol acetate, 5-HOMeC induced skin tumors in 90% of the animals, with 9.5 tumors/mouse. 5-MeC gave a 75% incidence of skin tumors with 6.2 tumors/mouse. The tumorigenic activities after a 10μg initiating dose were: 5-HOMeC, 45% skin tumor-bearing animals and 2.6 tumors/-mouse; 5-MeC, 55% skin tumor-bearing animals and 5.6 tumors/mouse. In contrast, 6-hydroxymethylchrysene was inactive. To investigate the mechanism of activation of 5-HOMeC, 3-fluoro-5-hydroxymethylchrysene (3-F-5-HOMeC) and 7-fluoro-5-hydroxymethylchrysene (7-F-5-HOMeC) were prepared and assayed for tumor initiating activity at a dose of 30 μg. (7-F-5-HOMeC) gave 95% tumor-bearing animals and 7.9 tumors/animal whereas 3-F-5-HOMeC gave only 5% tumor-bearing animals and 0.1 s/animal. The inhibition of tumorigenicity by substitution of fluorine at the 3-position, but not the 7-position of 5-HOMeC is strictly analogous to results obtained previously with 5-MeC and suggests a similar mechanism of activation for both compounds. The metabolites formed upon incubation of 5-HOMeC with cofactors and the 9000 × g supernatant from Aroclor pretreated rats were separated by h.p.l.c. The 1,2-dihydrodiol and 7,8-dihydrodiol of 5-HOMeC were identified. The major phenolic metabolite was identified as 1-hydroxy-5-hydroxymethylchrysene. In the in vitro metabolism of 7-F-5-HOMeC under the same conditions, we identified the 1,2-dihydrodiol but not the 7,8-dihydrodiol. In the metabolism of 3-F-5-HOMeC, oxidation in the 1-4 ring was inhibited relative to that observed in the metabolism of 5-HOMeC. These results suggest that 5-HOMeC is activated primarily through formation of its 1,2-dihydrodiol.

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