Effects of microsomal enzyme induction on toxicity of p-N, N-bis (2-chloroethyl)aminophenyl alkyl ethers in mice and survival times in L-1210 leukemic mice.
Four alkyl ethers of p-N,N-bis(2-chloroethyl)aminophenol were selected to study the effects of microsomal enzyme induction by phenobarbital on the toxicity changes as reflected by LD50 and alteration of survival times in L-1210 leukemic mice. In the phenobarbital pretreated mice the LD50 for the ethyl ether of p-N,N-bis(2-chloroethyl)aminophenol was decreased from 1641 to 1213 microns/kg. This result suggests that O-dealkylation is the major metabolic pathway. The LD50 for the propyl ether of p-N,N-bis(2-chloroethyl)aminophenol was increased by the pretreatment from 605 to 678 microns/kg. The LD50 for the butyl ether was increased from 714 to 910 microns/kg. An additional metabolic pathway, (omega-1)-hydroxylation, is suggested for the propyl and butyl ethers. The hexyl ether appeared to be unaffected by the pretreatment; thus, O-dealkylation was ruled out as a major pathway. In the survival studies, the pretreatment reduced the antitumor effectiveness of the ethyl and the butyl ethers. The survival times were increased for some dose levels for the propyl ether. No significant trend in survival times was observed for the hexyl ether in the pretreated mice.
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity*; D004790:Enzyme Induction / Q000187:drug effects*; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000201:enzymology; D051379:Mice; D008811:Mice, Inbred DBA; D008813:Mice, Inbred ICR; D008862:Microsomes, Liver / Q000201:enzymology*; D009368:Neoplasm Transplantation; D009588:Nitrogen Mustard Compounds / Q000627:therapeutic use / Q000633:toxicity*; D010634:Phenobarbital / Q000494:pharmacology
D000970:Antineoplastic Agents; D009588:Nitrogen Mustard Compounds; D010634:Phenobarbital