Buthionine sulfoximine (BSO) and N-(3,5-dichlorophenyl)succinimide nephrotoxicity: temporal aspects of BSO administration and BSO effects on renal transport systems.
The agricultural fungicide, N-(3,5-dichlorophenyl)succinimide (NDPS) induces acute polyuric renal failure which is attenuated by pretreatment with the glutathione depletors, diethyl maleate or buthionine sulfoximine (BSO). In the present study, the temporal aspects of BSO attenuation of NDPS nephrotoxicity were investigated. In addition, the ability of BSO to alter the renal accumulation of selected organic ions was examined as a possible mechanism for BSO's ability to attenuate NDPS nephrotoxicity. In the first set of experiments, NDPS (0.2 or 0.4 mmol/kg) or vehicle (sesame oil, 2.5 ml/kg) was administered intraperitoneally (i.p.) to groups of male Fischer 344 rats (4-8 rats/group) 0.25 or 2 h prior to BSO (890 mg/kg, i.p.) and renal function was monitored at 24 and 48 h. NDPS (0.4 mmol/kg) nephrotoxicity was markedly attenuated by administration of BSO at 0.25 h post-NDPS, but was not substantially altered by injection of BSO at 2 h post-NDPS. NDPS (0.2 mmol/kg)-induced renal effects were not potentiated by BSO injected at 0.25 h post-NDPS, and only 1 of 8 rats exhibited marked nephrotoxicity when BSO was administered at 2 h post-NDPS. In the second set of experiments, rats (4/group) were administered BSO (890 mg/kg, i.p.) or vehicle (0.9% saline, 10 ml/kg) and kidneys harvested at 2 or 5 h post-treatment. The ability of renal cortical slices to accumulate organic ions (p-aminohippurate [PAH], alpha-aminoisobutryic acid [AIB] or tetraethylammonium [TEA]) during a 90 min incubation was studied. Only TEA accumulation by renal cortical slices prepared from the 2 h post-treatment group was reduced. Studies were also conducted to examine the in vitro effects of BSO (10(-7)-10(-4) M) on the accumulation of PAH, AIB and TEA by renal cortical slices following 5, 15 or 90 min co-incubations of BSO and an organic ion BSO had no significant effects on the accumulation of any organic ion studied at any time point. These results indicate that BSO can still attenuate NDPS nephrotoxicity when administered at 0.25 h post-NDPS, but BSO loses effectiveness when given 2 h post-NDPS. These results also suggest that BSO is attenuating NDPS nephrotoxicity via glutathione depletion rather than altering renal accumulation of NDPS metabolites via renal PAH, TEA or AIB transporters.
Rankin
G O
GO
Department of Pharmacology, Marshall University School of Medicine, Huntington, WV 25704-9388, USA.
Beers
K W
KW
Teets
V J
VJ
Nicoll
D W
DW
Anestis
D K
DK
D000621:Aminoisobutyric Acids / Q000378:metabolism; D000818:Animals; D000963:Antimetabolites / Q000008:administration & dosage / Q000633:toxicity*; D001692:Biological Transport / Q000187:drug effects; D019328:Buthionine Sulfoximine / Q000008:administration & dosage / Q000633:toxicity*; D004334:Drug Administration Schedule; D005659:Fungicides, Industrial / Q000008:administration & dosage / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007672:Kidney Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D013388:Succinimides / Q000008:administration & dosage / Q000633:toxicity*; D019789:Tetraethylammonium; D013757:Tetraethylammonium Compounds / Q000378:metabolism; D013997:Time Factors
D000621:Aminoisobutyric Acids; D000963:Antimetabolites; D005659:Fungicides, Industrial; D013388:Succinimides; D013757:Tetraethylammonium Compounds; C100049:2-aminoisobutyric acid; C007352:N-(3,5-dichlorophenyl)succinimide; D019328:Buthionine Sulfoximine; D019789:Tetraethylammonium; D005978:Glutathione