4-AMINOAZOBENZENE AND N,N-DIMETHYL-4-AMINOAZOBENZENE AS EQUIPOTENT HEPATIC CARCINOGENS IN MALE C57BL[6XC3H]HEF1 MICE AND CHARACTERIZATION OF N-(DEOXYGUANOSIN-8-YL)-4-AMINOAZOBENZENE AS THE MAJOR PERSISTENT HEPATIC DNA-BOUND DYE IN THESE MICE

  • 1 January 1984
    • journal article
    • research article
    • Vol. 44  (6) , 2540-2550
Abstract
In contrast to the well-established requirement for an N-methyl group for efficient hepatic tumor induction by dietary administration of derivatives 4-aminoazobenzene (AB) to adult rats, AB and its N-methyl and N,N-dimethyl derivatives have high and approximately equal hepatocarcinogenicity when given as a single i.p. dose to male 12-day-old C57BL/6 .times. C3H/He F1 (B6C3F1) mice. The hepatoma multiplicity induced by these dyes was approximately linearly related to the dose from 0.017 to 0.15 .mu.mol/g body weight; at the high dose, an average of 11 hepatomas per mouse was observed at 10 mo. Female B6C3F1 mice were resistant to tumor induction under these conditions. AB and its N-methyl derivative also induced the same incidences of hepatomas on administration of a single dose of 0.45 .mu.mol/g body weight to 12-day-old male C3H/He mice (about 15 hepatomas per mouse) or C57BL/6 mice (about 1 hepatoma per mouse). Infant male Fischer rats were much less susceptible; < 25% of the rats given 4 i.p. injections (0.3 to 0.4 .mu.mol/g of body weight per injection) of N-methyl-4-amino-azobenzene and .ltoreq. 5% of those given these doses of N,N-dimethyl-4-aminoazobenzene or AB before 22 days of age developed hepatic carcinomas by 24 mo. Reverse-phase high-performance liquid chromatography of enzymatically hydrolyzed hepatic DNA from 12-day-old male B6C3F1 mice or Fischer rats given an i.p. dose (0.08 or 0.3 .mu.mol/g of body weight) of [prime-ring-3H]AB showed a single major adduct which was chromatographically identical to N-(deoxy-guanosin-8-yl)-4-aminoazobenzene synthesized by reaction at pH 7 of N-acetoxy-4-aminoazobenzene (formed in situ from N-hydroxy-4-aminoazobenzene and acetic anhydride) with deoxyguanosine. Mouse and rat liver DNA contained 20 and 0.5 pmol, respectively, of this adduct per mg 24 h after administration of 0.3 .mu.mol of [prime-ring-3H]AB/g of body weight. At 24 h after administration of N,N-[prime-ring-3H]dimethyl-4-aminoazobenzene to male B6C3F1 mice, N-(deoxyguanosin-8-yl)-4-aminoazobenzene, N-(deoxyguanosin-8-yl)-N-methyl-4-aminoazobenzene, and 3-(deoxyguanosin-N2-yl)-N-methyl-4-aminoazobenzene were present in ratio of approximately 4:2:1, respectively. Unlike the N-(deoxyguanosin-8-yl)-N-methyl-4-aminoazobenzene adducts, the N-(deoxyguanosin-8-yl)-4-aminoazobenzene adducts were relatively stable in the DNA; the level of the latter adducts decreased about 60% between 24 h and 21 days. Adducts from N,N-[prime-ring-3H]dimethyl-4-aminoazobenzene were formed at much lower levels in hepatic DNA of preweanling rats than in that of preweanling mice; (N-deoxyguanosin-8-yl)-N-methyl-4-aminoazobenzene was the major adduct in the rat liver DNA.

This publication has 13 references indexed in Scilit: