Newly synthesized dithiocarbamates inhibit the metabolism and toxicity of N-nitrosodimethylamine.
Several dithiocarbamates (DTC) of secondary amines and secondary amino acids were tested for their stability in aqueous solution and for their effect on nitrosamine metabolizing enzymes and on the acute toxicity of N-nitrosodimethylamine (NDMA) in rats. The following results were found: (i) All DTC tested were stable in alkaline solution; in acidic milieu, only DTC derived from secondary amino acids were moderately stable. (ii) The activity of NDMA-demethylase in rat liver microsomes was inhibited completely by all DTC tested. (iii) The excretion of unmetabolized NDMA in rat urine over 24 h increased from 0.1% without pretreatment to 3.6% of the given NDMA dose when combined with a single dose of DTC. (iv) The acute toxicity of NDMA was reduced by dihydroxyethyldithiocarbamate; when the sulfur compound was administered simultaneously and 24 h after the nitrosamine, lethality was almost completely inhibited. (v) The stability of a compound in aqueous solutions did not affect its activity in the enzyme tests.
Frank
N
N
German Cancer Research Centre, Institute of Toxicology and Chemotherapy, Heidelberg.
Bertram
B
B
Scherf
H R
HR
Wiessler
M
M
D000818:Animals; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D004128:Dimethylnitrosamine / Q000378:metabolism* / Q000633:toxicity; D004050:Ditiocarb / Q000494:pharmacology* / Q000031:analogs & derivatives; D004355:Drug Stability; D010089:Oxidoreductases, N-Demethylating / Q000032:analysis; D051381:Rats; D012521:Sarcosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013859:Thiocarbamates / Q000494:pharmacology*
D013859:Thiocarbamates; C055171:sarcosine dithiocarbamate; D003577:Cytochrome P-450 Enzyme System; D004050:Ditiocarb; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating; C039353:dihydroxyethyldithiocarbamate; D004128:Dimethylnitrosamine; D012521:Sarcosine