Dual protective role for glutathione S-transferase class pi against VCD-induced ovotoxicity in the rat ovary.
The occupational chemical 4-vinylcyclohexene diepoxide (VCD) selectively destroys ovarian small pre-antral follicles in rats and mice via apoptosis. Detoxification of VCD can occur through glutathione conjugation, catalyzed by glutathione S-transferase (GST) enzymes. Further, GST class pi (GSTp) can negatively regulate JNK activity through protein:protein interactions in extra-ovarian tissues. Dissociation of this protein complex in the face of chemical exposure releases the inhibition of pro-apoptotic JNK. Increased JNK activity during VCD-induced ovotoxicity has been shown in isolated ovarian small pre-antral follicles following in vivo dosing of rats (80mg/kg/day; 15days, i.p.). The present study investigated the pattern of ovarian GSTp expression during VCD exposure. Additionally, the effect of VCD on an ovarian GSTp:JNK protein complex was investigated. PND4 F344 rat ovaries were incubated in control medium+/-VCD (30muM) for 2-8days. VCD increased ovarian GSTp mRNA (P <0.05) relative to control on d4-d8; whereas GSTp protein was increased (P<0.05) on d6-d8. A GSTp:JNK protein complex was detected by immunoprecipitation and Western blotting in ovarian tissues. Relative to control, the amount of GSTp-bound JNK was increased (P=0.09), while unbound JNK was decreased (P<0.05) on d6 of VCD exposure. The VCD-induced decrease in unbound JNK was preceded by a decrease in phosphorylated c-Jun which occurred on d4. These findings are in support of a possible dual protective role for GSTp in the rat ovary, consisting of metabolism of VCD and inhibition of JNK-initiated apoptosis.
Keating
Aileen F
AF
Department of Physiology, University of Arizona, Tucson, AZ 85724, USA.
Sen
Nivedita
N
Sipes
I Glenn
IG
Hoyer
Patricia B
PB
D000818:Animals; D053138:Cyclohexenes / Q000633:toxicity*; D005260:Female; D051549:Glutathione S-Transferase pi / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D010053:Ovary / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D014753:Vinyl Compounds / Q000633:toxicity*
D053138:Cyclohexenes; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D014753:Vinyl Compounds; C012606:4-vinyl-1-cyclohexene dioxide; D051549:Glutathione S-Transferase pi; D048031:JNK Mitogen-Activated Protein Kinases