Genetic differences in the metabolic activation of benzo[a]pyrene in mice. Attempts to correlate tumorigenesis with binding of reactive intermediates to DNA and with mutagenesis in vitro

O. Pelkonen, A. R. Boobis, R. C. Levitt, R. E. Kouri, D. W. Nebert

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

The carcinogenesis index of subcutaneous benzo[a]pyrene-initiated fibrosarcomas in the genetically 'responsive' C3H inbred mouse strain is more than five times higher, and about 15 times higher, than that in the 'responsive' C57BL/6 and the 'nonresponsive' DBA/2 strains, respectively. Carcinogenesis indices involving F 1 hybrids of these strains indicate that additional genes besides the Ah locus may cause a particular inbred strain to be more sensitive, or resistant, to benzo[a]pyrene-initiated tumors than would be expected solely on the basis of aryl hydrocarbon (benzo[a]pyrene) hydroxylase (EC 1.14.14.2) inducibility. The DNA-bound benzo[a]pyrene metabolite complexes generated by mouse liver or skin microsomes in vitro can be resolved into at least nine distinct peaks by elution of a Sephadex LH-20 column with a water-methanol gradient. Eight peaks, shown previously to be associated with increased hepatic cytochrome P 1-450 content, are greater with liver microsomes from genetically responsive C3H and C57BL/6 inbred strains and the (C57BL/6)(C3H)F 1, (C3H)(DBA/2)F 1 and (C57BL/6)(DBA/2)F 1 hybrids than from the genetically nonresponsive DBA/2 inbred strain. All nine peaks are greater with skin microsomes in vitro from C3H and C57BL/6 than from DBA/2 mice. Benzo[a]pyrene mutagenicity in vitro with Salmonella typhimurium tester strain TA98 is increased 5- to 6-fold with liver microsomes from C3H and C57BL/6 inbred mice and the three F 1 hybrids mentioned above, compared with liver microsomes from DBA/2 mice. Similar genetic differences in benzo[a]pyrene mutagenesis with the bacterial tester strain TA100 are also seen. DNA 'repair' - as measured by the rate at which DNA-bound benzo[a]pyrene 4,5-oxide and the 7,8-diol-9,10-epoxides are removed from mouse skin DNA - is not significantly different between C3H and C57BL/6 mice. The K-region oxide appears to be removed from DNA nucleosides, however, at least twice as rapidly as the 7,8-diol-9,10-epoxides. Our data thus demonstrate a strikingly good correlation between genetically determined increases in peaks representing P 1-450-catalyzed benzo[a]pyrene metabolites bound to DNA and benzo[a]pyrene mutagenesis in vitro. Neither of these in vitro parameters, nor DNA repair in mouse skin in vivo, however, explains the 5- to 6-fold difference in benzo[a]pyrene carcinogenesis index between the two genetically responsive strains, C3H and C57BL/6.

Original languageEnglish (US)
Pages (from-to)281-293
Number of pages13
JournalPharmacology
Volume18
Issue number6
DOIs
StatePublished - Jan 1 1979
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology

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