Suppression of humoral immune responses by dialkylnitrosamines: structure-activity relationships

Comparisons between chemical structure of N,N-dialkylnitrosamine congeners and their ability to alter the Day 4 IgM antibody response to sRBC, body weights, and organ weights of female B6C3F1 mice were investigated. Short-chain nitrosamine congeners were selected for these studies on the basis of two criteria: (1) congeners with symmetrical aliphatic chain length [N-nitrosodimethylamine (DMN), N-nitrosodiethylamine (DEN), N-nitrosodipropylamine (DPN), N-nitrosodibutylamine (DBN)] and (2) congeners possessing an N-methyl group [N-nitrosomethylethylamine (MEN), N-nitrosomethylpropylamine (MPN), and N-nitrosomethylbutylamine (MBN)]. The immunotoxicity of each congener was evaluated based on the compound's ability to suppress the in vivo sRBC antibody response following 7 consecutive days of treatment. An ED50 dose was calculated, using a linear regression analysis, for each congener and represents the millimoles of congener per kilogram body weight required to cause a 50% suppression of the sRBC response. These studies demonstrated two general trends: (1) those dialkylnitrosamine congeners that possessed an N-methyl group were most immunotoxic and exhibited comparable ED50 concentrations (42-183 mumol/kg); and (2) dialkylnitrosamine congeners possessing symmetrical aliphatic chains demonstrated an inverse relationship between aliphatic chain length and immunotoxic potency--DMN (62 mumol/kg) greater than DEN (276 mumol/kg) greater than DPN (467 mumol/kg) greater than DBN (1557 mumol/kg). Comparisons were also made between the immunotoxic potency of various nitrosamine congeners in the whole animal and their potency in an in vitro hepatocyte-spleen cell coculture system.