Effects of fluorine substitution on the tumor initiating activity and metabolism of 5-hydroxymethylchrysene, a tumorigenic metabolite of 5-methylchrysene.
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 microgram, 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 10 microgram 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-hydroxy-methylchrysene 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 microgram. 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 x 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.
D000818:Animals; D002273:Carcinogens / Q000378:metabolism*; D002911:Chrysenes / Q000378:metabolism* / Q000633:toxicity; D005260:Female; D005461:Fluorine; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D009374:Neoplasms, Experimental / Q000139:chemically induced; D010616:Phenanthrenes / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D013329:Structure-Activity Relationship; D013347:Subcellular Fractions / Q000378:metabolism; D013997:Time Factors
D002273:Carcinogens; D002911:Chrysenes; D010616:Phenanthrenes; D005461:Fluorine; C032670:5-hydroxymethylchrysene; C008422:5-methylchrysene