Reduction of tumorigenicity and of dihydrodiol formation by fluorine substitution in the angular rings of dibenzo(a,i)pyrene.

Abstract

The tumor-initiating activities on mouse skin and in vitro metabolism of dibenzo(a,i)pyrene, 2-fluorodibenzo(a,i)pyrene, 3-fluorodibenzo(a,i)pyrene, and 2, 10-difluorodibenzo(a,i)pyrene were compared. After an initiating dose of 500 micrograms, followed by promotion with tetradecanoylphorbol acetate, dibenzo(a,i)pyrene induced skin tumors in 85% of the mice and caused 5.8 skin tumors/mouse. The corresponding tumorigenic activities for the fluorinated compounds were: 2-fluorodibenzo(a,i)pyrene (85%; 1.7 tumors/mouse); 3-fluorodibenzo(a,i)pyrene (80%; 3.1 tumors/mouse); and 2,10-difluorodibenzo(a,i)pyrene (10%; 0.1 tumors/mouse). After an initiating dose of 100 micrograms, only dibenzo(a,i)pyrene showed significant tumor-initiating activity. 3,4-Dihydro-3,4-dihydroxydibenzo(a,i)pyrene was identified as a metabolite of dibenzo(a,i)pyrene formed by the 9000 X g supernatant from the livers of Aroclor 1254-pretreated rats. Another dihydrodiol was tentatively identified as 1,2-dihydro-1,2-dihydroxydibenzo(a,i)pyrene. The formation of these angular ring dihdrodiols was inhibited in the metabolism of 2-fluorodibenzo(a,i)pyrene and 3-fluorodibenzo(a,i)pyrene. Angular ring dihydrodiols were not detected in the metabolism of 2,10-difluorodibenzo(a,i)pyrene. These results suggest that an angular ring dihydrodiol, 3,4-dihydro-3,4-dihydroxydibenzo(a,i)pyrene, which can form a bay-region dihydrodiol epoxide, may be a proximate carcinogen of dibenzo(a,i)pyrene.

• Authors: S S Hecht, E J LaVoie, V Bedenko, L Pingaro, S Katayama, D Hoffmann, D J Sardella, E Boger, R E Lehr
• Journal: Cancer research (Cancer Res) Vol. 41 Issue 11 Pt 1 Pg. 4341-5 (Nov 1981) ISSN: 0008-5472 [Print] United States
• PMID: 7306963 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Aroclors
• Benzopyrenes
• Carcinogens
• Dihydroxydihydrobenzopyrenes
• Chlorodiphenyl (54% Chlorine)
• 3-fluorobenzo(a,i)pyrene
• 2,10-difluorobenzo(a,i)pyrene
• 2-fluorobenzo(a,i)pyrene
• dibenzo(a,i)pyrene
• 3,4-dihydro-3,4-dihydroxybenzo(a,i)pyrene

Topics

• Animals
• Aroclors (pharmacology)
• Benzopyrenes (biosynthesis, toxicity)
• Biotransformation
• Carcinogens
• Chlorodiphenyl (54% Chlorine)
• Chromatography, High Pressure Liquid
• Dihydroxydihydrobenzopyrenes
• Female
• Liver (drug effects, metabolism)
• Male
• Mice
• Neoplasms, Experimental (chemically induced, metabolism)
• Rats
• Skin Neoplasms (chemically induced, metabolism)