In vitro macromolecular binding of 2-(2-chlorophenyl)-2-(4-chlorophenyl)-1,1-dichloroethane (o,p'-DDD) in the mouse lung and liver.
The activation and covalent binding of 14C-labelled 2-(2-chlorophenyl)-2-(4-chlorophenyl)-1,1-dichloroethane (o,p'-DDD) in mouse lung and liver S-9 preparations were examined in vitro. These results showed an oxidative cytochrome P-450 mediated transformation of o,p'-DDD to metabolite(s) that bind covalently to proteins, phospholipids and to added naked DNA in both lung and liver. The apparent Km-values for the covalent binding of o,p'-DDD to protein were 0.25 microM and 3.30 microM in lung and liver, respectively. Addition of glutathione to the incubation medium decreased the binding of o,p'-DDD more efficiently in the liver than in the lung. Thus, the selective lung binding of o,p'-DDD previously observed in vivo seems to result from an in situ activation. The tissue selectivity in vivo is suggested to be due to the low apparent Km in the lung favouring bioactivation at low, ecotoxicologically relevant doses, as well as to a less pronounced protection by glutathione in the lung.
Lund
B O
BO
Department of Pharmacology and Toxicology, Swedish University of Agricultural Sciences, Uppsala Biomedical Centre.
Bergman
A
A
Brandt
I
I
D000818:Animals; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D004247:DNA / Q000378:metabolism; D005260:Female; D005978:Glutathione / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000032:analysis / Q000378:metabolism*; D008168:Lung / Q000032:analysis / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008939:Mitotane / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism; D011485:Protein Binding
D010743:Phospholipids; D008939:Mitotane; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D005978:Glutathione