Structure-activity relationship for two lipoxygenase inhibitors and their potential for inducing nephrotic syndrome.
In a study of structure-activity relationship with drug-induced nephropathy two lipoxygenase inhibitors, the N-hydroxyurea derivative 70C ((E)-N-{3-[3-(4-fluorophenoxy) phenyl]-1-(R, S)-methylprop-2-enyl}-N-hydroxyurea) and the N-hydroxamic acid analogue 360C ((E)-N-{3-[3-(4-fluorophenoxy) phenyl]-1-(R, S)-methylprop-2-enyl}-N-hydroxamic acid), were administered to rats. 70C and 360C were dosed to female Wistar rats at 100 mg/kg po daily for 7 days. Another group of rats was given a single intravenous bolus dose of puromycin aminonucleoside (PAN) at 100 mg/kg. Urine samples were collected from all groups during the study and plasma samples were collected after 7 days. Kidneys were excised and fixed for examination by electron microscopy. 70C- and PAN-treated groups both showed early changes in the glomeruli, in which the visceral cells appeared enlarged and showed varying degrees of foot process loss. This foot process loss was associated with decreases in total plasma protein and albumin and increases in the plasma cholesterol, triglycerides, creatinine, and urea were recorded. Marked proteinuria was observed in both the 70C and PAN groups. The foot process loss together with increased proteinuria, hypoalbuminemia, hypercholesterolemia, and lipemia are all characteristic of the human condition, Minimal Change Nephrotic Syndrome. All the biochemical and morphological investigations showed that 360C-treated rats were similar to the control group, suggesting that the hydroxyurea moiety of 70C is responsible, either directly or indirectly, for the induction of the nephrotic syndrome seen in rats.
Morley
T J
TJ
Glaxo-Wellcome, Langley Court, Beckenham, Kent, BR3 3BS, United Kingdom.
Evans
G O
GO
Goodwin
D A
DA
Read
N G
NG
Hodgson
S T
ST
Hawksworth
G M
GM
D000284:Administration, Oral; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D001798:Blood Proteins / Q000032:analysis; D002784:Cholesterol / Q000097:blood; D003404:Creatinine / Q000097:blood / Q000652:urine; D004195:Disease Models, Animal; D005260:Female; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity* / Q000652:urine; D006918:Hydroxyurea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000633:toxicity / Q000652:urine; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000503:physiopathology / Q000648:ultrastructure; D016859:Lipoxygenase Inhibitors / Q000633:toxicity*; D009402:Nephrosis, Lipoid / Q000139:chemically induced* / Q000503:physiopathology; D009404:Nephrotic Syndrome / Q000097:blood / Q000139:chemically induced* / Q000652:urine; D011507:Proteinuria / Q000139:chemically induced / Q000652:urine; D011692:Puromycin Aminonucleoside / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014280:Triglycerides / Q000097:blood; D016482:Urinalysis
D000903:Antibiotics, Antineoplastic; D001798:Blood Proteins; D006877:Hydroxamic Acids; D016859:Lipoxygenase Inhibitors; C108870:N-(3-(3-(4-fluorophenoxy)phenyl)-1--methylprop-2-enyl)-N-hydroxamic acid; D014280:Triglycerides; C080871:BW B70C; D011692:Puromycin Aminonucleoside; D002784:Cholesterol; D003404:Creatinine; D006918:Hydroxyurea