Differential mutagenicity of two dihydrophenalene congeners: examination of formaldehyde generation and reactive intermediate formation as possible mechanisms.
Compounds in the dihydrophenalene series are currently under investigation as potential antipsychotic agents. The mutagenicity of two compounds in this series was evaluated in several strains in the Ames Salmonella (2,3-dihydro-N,N-dimethyl-1H-phenalen-2-amine:HCI) was less mutagenic than its monomethyl analogue, U-64,273A. Two hypothesis-the of formaldehyde and release of formaldehyde and the formation of macromolecular reactive intermediates--were evaluated as possible mechanisms for the observed mutagenicity. Formaldehyde release during biotransformation of U-65,556A but not U-64,273 was demonstrated, as measured by trapping with the Nash reagent. Thus, formaldehyde release does not correlate with the mutagenic potency of these compounds. Covalent binding of U-65,556A-[3H] equivalents to rat hepatic protein was observed, but binding to DNA, which is considered the more critical target molecule, was not observed. These data suggest that reactive intermediate formation does not explain the mutagenicity of U-65,556A in the Ames Salmonella assay. Follow-up studies were conducted to assess the possible contribution of tritium exchange to the observed covalent binding to protein by quantitatively recovering 3H2O from incubations containing U-65,556A-[3H] and rat liver microsomes. Data indicate that enzyme-dependent formation of 3H2O does occur but that this phenomenon does not account for U-65,556A-[3H]-derived, protein-bound tritium in covalent binding studies.
Petry
T W
TW
Investigative Toxicology Research Unit, Upjohn Company, Kalamazoo, MI 49001.
Jolly
R A
RA
Aaron
C S
CS
Schwende
F J
FJ
D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000378:metabolism; D005557:Formaldehyde / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009152:Mutagenicity Tests / Q000379:methods; D009249:NADP / Q000378:metabolism; D043803:Phenalenes; D011083:Polycyclic Compounds / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D014316:Tritium; D014867:Water / Q000378:metabolism
D043803:Phenalenes; D011083:Polycyclic Compounds; D011506:Proteins; D014867:Water; D014316:Tritium; C068246:U 65556A; D005557:Formaldehyde; C068245:U 64273A; D009249:NADP; D004247:DNA