Induction of reproductive system tumors in mice by N⁶‐(methylnitroso)‐adenosine and a tumorigenic effect of its combined precursors

Abstract

Interaction of the naturally-occurring nucleoside, N6-methyl adenosine, with nitrite, a reaction that occurs readily under acidic conditions, results in the formation of a nitrosamine, N6-(methylnitroso) adenosine[m6(NO)Ado]. This nitrosamine was given in the drinking water (1 mM solution) of non-inbred Swiss mice from 3 weeks of age until death. It caused a significant increase in the incidence of primary lung tumors, compared with controls. It also induced reproductive tract tumors in 80% of the exposed females, including mammary tumors in 60% and uterine tumors in 25%. The precursors of m6(NO) Ado, m6Ado and nitrite, did not elevate tumor incidence when given singly, but when administered together resulted in a significant increase in numbers of lung tumors in the males. The nitrosamine base, N6-(methylnitroso)adenine, was found to be a less potent carcinogen than m6(NO)Ado, causing lung tumors only in males and possibly a few mammary tumors in females. These results indicate the in vivo formation of a carcinogen from m6Ado and nitrite, and show that m6(NO)Ado induces neoplasms in the reproductive system of mice, an unusual target for a N-nitroso carcinogen.

Practical and Science-Based Strategy for Establishing Acceptable Intakes for Drug Product N-Nitrosamine Impurities

“…There is no unique CAS number provided for N 6 -(methylnitroso)adenosine. The data presented in LCDB do correspond to that for N 6 -(methylnitroso)adenosine from Anderson et al 31 e When a user enters CAS number 21928-82-5 into LCDB, it will pull back a record of carcinogenicity data associated with N 6 -methyladenosine. However, this CAS number is associated with N 6 -(methylnitroso)adenine in CAS and one must refer to the source document 31 to find the relevant carcinogenicity data for N 6 -(methylnitroso)adenine.…”

“…The data presented in LCDB do correspond to that for N 6 -(methylnitroso)­adenosine from Anderson et al e When a user enters CAS number 21928-82-5 into LCDB, it will pull back a record of carcinogenicity data associated with N 6 -methyladenosine. However, this CAS number is associated with N 6 -(methylnitroso)­adenine in CAS and one must refer to the source document to find the relevant carcinogenicity data for N 6 -(methylnitroso)­adenine. f TD 50 calculated. g No data reported in the LCDB or the CPDB. h LCDB, Lhasa Carcinogenicity Database; TD 50 , dose producing a 50% tumor incidence. …”

“…There is no unique CAS number provided for N 6 -(methylnitroso)­adenosine. The data presented in LCDB do correspond to that for N 6 -(methylnitroso)­adenosine from Anderson et al…”

“…The data presented in LCDB do correspond to that for N 6 -(methylnitroso)adenosine from Anderson et al 31 e When a user enters CAS number 21928-82-5 into LCDB, it will pull back a record of carcinogenicity data associated with N 6 -methyladenosine. However, this CAS number is associated with N 6 -(methylnitroso)adenine in CAS and one must refer to the source document 31 to find the relevant carcinogenicity data for N 6 -(methylnitroso)adenine. f TD 50 calculated.…”

Strategies for Assessing Acceptable Intakes for Novel N-Nitrosamines Derived from Active Pharmaceutical Ingredients

“…The two N-nitrosamine nucleoside derivatives have been tested for induction of tumors in male and female CD-1 mice after a lifetime of exposure, 4 times per week in drinking water. 138 The nitrosamine base, N6-methylnitrosoadenine, was found to cause lung tumors (only in males) and possibly mammary tumors in females. The most sensitive effect was the induction of lung tumors in male mice with a TD 50 of 18 mg/ kg/day (95% confidence interval (CI) of 9.09−51.3 mg/kg/ day; calculated using the R-code adopted from Lhasa Limited 58 ).…”