Enhancement of SDZ ICT 322-induced cataracts and skin changes in rats following vitamin E- and selenium-deficient diet.
The indole-3-carboxylic acid scopoine ester. SDZ ICT 322, is a selective hydroxytryptamine (5-HT3) antagonist, which after chronic treatment causes posterior subcapsular cataracts and skin changes such as hair loss, hyperaemia, desquamation and hyperkeratosis in rats. The detailed mechanisms underlying these changes are not yet known. In order to evaluate a possible oxidative stress-induced pathomechanism of SDZ ICT 322, the antioxidative defence capacity in rats was modulated by feeding a special vitamin E- and selenium-deficient (VE/SeD) diet. For this purpose 32 male Wistar rats, age 4 weeks, were pretreated for 8 weeks with either a VE/SeD diet or a normal standard diet. Each dietary group was divided into 8 control and 8 SDZ ICT 322-treated animals. SDZ ICT 322 was administered in feed to rats at an adjusted daily dose level of 125 mg/kg for 14 weeks. Plasma levels of SDZ ICT 322 as well as of the N-desmethyl metabolite were similar in rats fed the different diets in weeks 3, 6 and 14. In SDZ ICT 322 treated VE/SeD rats cataracts were observed by week 7, whereas in rats fed normal diet cataracts were first seen in week 14. In the normal dietary group no corneal opacity was found after SDZ ICT 322-treatment; however, a corneal opacity was seen in the deficiency group in parallel with one of the cataract animals in week 7. The incidence and severity of clinical skin signs were greater and their onset was earlier in the deficiency dietary group: onset occurred after 6 weeks compared to 9 weeks on the normal diet. Thiobarbituric acid reactive substances, an indicator mainly of oxidized lipids, were statistically significantly increased in the urine of rats administered SDZ ICT 322 and the VE/SeD diet. Uric acid, which is an endogenous antioxidant was statistically significantly decreased in the urine and plasma of SDZ ICT 322 VE/SeD treated rats. The clinical eye and skin changes occurring early after VE/SeD feeding, the unchanged drug plasma exposure and unchanged drug metabolite formation in combination with the general pro-oxidative activity of the drug suggest an oxidative stress-mediated pathomechanism of SDZ ICT 322 at high dose levels in rats.
Längle
U W
UW
Sandoz Pharma Ltd., Drug Safety Department, Basle, Switzerland.
Wolf
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Cordier
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D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002386:Cataract / Q000139:chemically induced*; D004435:Eating / Q000187:drug effects; D007211:Indoles / Q000097:blood / Q000633:toxicity*; D008297:Male; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012643:Selenium / Q000172:deficiency*; D012702:Serotonin Antagonists / Q000097:blood / Q000633:toxicity*; D012867:Skin / Q000187:drug effects*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014527:Uric Acid / Q000097:blood / Q000652:urine; D014811:Vitamin E Deficiency / Q000378:metabolism*
D007211:Indoles; D012702:Serotonin Antagonists; D017392:Thiobarbituric Acid Reactive Substances; C084870:SDZ ICT 322; D014527:Uric Acid; D012643:Selenium