Influence of the carboxylesterase inhibitor bis-p-nitrophenylphosphate on the rates of hydrolysis of various alpha-esters of 1-(N-methyl-N-nitrosamino)-methanol in vitro and in vivo and on the acute toxicity and carcinogenicity of 1-(N-methyl-N-nitrosamino)-methylacetate.
The effect of an in vivo treatment with the carboxylesterase inhibitor bis-p-nitrophenylphosphate (BNPP) on the hydrolysis of 1-(N-methyl-N-nitrosamino)-methylacetate (NNMA), 1-(N-methyl-N-nitrosamino)-methylbutyrate (NNMB), 1-(N-methyl-N-nitrosamino)-methylbenzoate (NNMBz) and 1-(N-methyl-N-nitrosamino)-methylpivaloate (NMMP) in rat tissue homogenates was studied. The rates of hydrolysis were specific for each compound and different in every organ tested; the extent of inhibition of the hydrolysis by BNPP was also substrate and organ specific. In some cases no inhibition at all was observed. The rate of elimination of NNMA, NNMB, and NNMP from blood was not influenced by BNPP pretreatment. The LD50 of NNMA after i.v. application showed a rise of 85% with a BNPP pretreatment. BNPP also influenced the carcinogenicity of NNMA, whereby the total carcinogenic potency was not altered, but the organotropism had changed slightly.
N
N
Frank
R
R
Caesar
H R
HR
Scherf
M
M
Wiessler
D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors*; D002273:Carcinogens; D004128:Dimethylnitrosamine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006207:Half-Life; D006868:Hydrolysis; D007928:Lethal Dose 50; D008297:Male; D009374:Neoplasms, Experimental / Q000139:chemically induced; D009596:Nitrophenols / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D002273:Carcinogens; D009596:Nitrophenols; C014659:methyl(acetoxymethyl)nitrosamine; C002887:bis(4-nitrophenyl)phosphate; D002265:Carboxylic Ester Hydrolases; D004128:Dimethylnitrosamine