Neutrophil activation by polychlorinated biphenyls: structure-activity relationship.
Polychlorinated biphenyls (PCBs) rapidly stimulate polymorphonuclear leukocytes (neutrophils) in vitro to produce superoxide anion (O2-). This response results from activation of various intracellular signal transduction pathways and appears to occur in a structure-specific fashion. Individual PCB congeners, varying in pattern and extent of chlorination, were tested for their ability to stimulate production of O2- and/or to enhance the response to protein kinase C activation by phorbol myristate acetate (PMA). Neutrophils were isolated from retired breeder, male, Sprague-Dawley rats and exposed to either vehicle, 10 or 50 microM PCB for 30 min at 37 degrees C. PMA (0 or 20 ng/ml) was added for an additional 10 min, and O2- generated during the incubation period was measured. 2,2'-Dichlorobiphenyl (2,2'-DCB), 2,4'-DCB, or 3,3'-DCB (50 microM) stimulated neutrophils to produce O2-. Incubation of neutrophils with 4,4'-DCB, 3,3',4,4',5-pentachlorobiphenyl (3,3',4,4',5-PeCB), 3,3',4,5,5'-PeCB, or 2,2',3,3',4,4'-hexachlorobiphenyl (2,2',3,3',4,4'-HCB) did not result in generation of O2-. Of the various congeners, 2,4'-DCB elicited the greatest production of O2-. Exposure to 10 microM 2,2'-DCB, 2,4'-DCB, 3,3'-DCB, or 2,2',3,3',4,4'-HCB prior to addition of PMA caused a significant increase in the amount of O2- produced, greater than that seen with either compound alone. PMA-stimulated O2- production was unaffected by prior exposure to 4,4'-DCB, 3,3',4,4',5-PeCB, or 3,3',4,5,5'-PeCB. In separate experiments, 3,3',4,4',5-PeCB inhibited the amount of O2- produced in response to activation with either 3,3'-DCB or 2,4'-DCB. Thus, it appears that congeners which are noncoplanar are capable of stimulating neutrophil O2- production. Coplanar congeners with high affinity for the Ah receptor do not activate neutrophils to produce O2- and may inhibit this response. These results are consistent with the hypothesis that PCBs stimulate neutrophil O2- production by a mechanism that is structure-specific and dependent on the chlorine substitution pattern of the biphenyl rings. Molecular modeling suggested that the sum of atomic charges on chlorine atoms is the most important descriptor for congeners which stimulate O2- production. The angle of rotation and the difference in energy between the highest occupied molecular orbital and the lowest unoccupied molecular orbital are integrative descriptors which, along with the sum of chlorine atomic charges, are associated with this biological activity.
Brown
A P
AP
Department of Pharmacology and Toxicology, Michigan State University, East Lansing 48824, USA.
Olivero-Verbel
J
J
Holdan
W L
WL
Ganey
P E
PE
D000818:Animals; D066298:In Vitro Techniques; D008297:Male; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D011078:Polychlorinated Biphenyls / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013481:Superoxides / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D013481:Superoxides; D011078:Polychlorinated Biphenyls; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate