Cytochrome P-450-dependent formation of ethylene from N-nitrosoethylamines

Ethylene was identified as a metabolite of N-nitrosodiethylamine (NDEA) as well as of N-nitrosomethylethylamine and N-nitrosoethylbutylamine. The formation of ethylene from these carcinogenic compounds is cytochrome P-450- and NADPH-dependent. With NDEA, the rate of the reaction in rabbit liver microsomes is increased by treatment of the animals with phenobarbital or ethanol, which are known to induce the synthesis of P-450 form 2 and P-450 form 3a (P-450ALC), respectively, and the activity is inhibited by anti-P-450 form 2 or form 3a IgG. The rate of ethylene formation is about 10-fold higher in nasal microsomes than in hepatic microsomes. In a reconstituted system, P-450 form 3a is the most active in ethylene formation from NDEA, followed by forms 2 and 4. It has been proposed by others that the alpha-hydroxylation of N-nitrosodialkylamines leads to the formation of an aldehyde and an alkyl diazonium ion, which, with the loss of N2, yields an alkyl carbonium ion capable of producing the corresponding alcohol or binding macromolecules through electrophilic reactions. In the case of the N-nitrosoalkylethylamines we have studied, the ethyl carbonium ion produced could, in addition, generate ethylene by proton elimination.