Effects of glutathione depletion on the acute nephrotoxic potential of arsenite and on arsenic metabolism in hamsters.
Our previous study showed that pretreatment with buthionine sulfoximine (BSO), which inhibits glutathione synthesis, results in acute renal failure with oliguria in hamsters ingesting sodium arsenite (5 mg As/kg). For a deeper understanding of the relationship between arsenic metabolism and the subsequent development of nephrotoxicity, we studied excretion, tissue retention, biotransformation, pharmacokinetics, and histopathological events in the kidneys of hamsters both with and without BSO pretreatment. The total amount of arsenic excreted in the urine and feces within 72 hr of arsenite administration was more than fivefold lower in BSO-pretreated animals than in the controls without pretreatment (9.2 versus 53.4% of the arsenic dose). The persistence of high amounts of total arsenic was apparent in the blood, liver, and kidneys of BSO-pretreated hamsters, even though the content of inorganic arsenic steadily decreased with time. The disappearance of inorganic arsenic from the blood showed a biphasic elimination pattern characterized first by a rapid component with a half-life of 4.5 hr and second by a slower component with a half-life of 58.0 hr in the BSO-pretreated hamsters, while these half-lives were 0.6 and 11.0 hr, respectively, in the controls. BSO pretreatment not only impaired the excretion of inorganic arsenic, but also impaired its methylation. Combined BSO/arsenite treatment resulted in renal tubular necrosis which was prominent at 1 hr after arsenite administration. By 1 hr, the renal content of inorganic arsenic in the BSO-pretreated animals was 1.7 times higher than that in the controls. This study demonstrates that glutathione depletion elicits the nephrotoxic manifestations of arsenic poisoning.
Hirata
M
M
Department of Hygiene, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Tanaka
A
A
Hisanaga
A
A
Ishinishi
N
N
D000818:Animals; D001151:Arsenic / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D018053:Arsenites; D006224:Cricetinae; D005243:Feces / Q000737:chemistry; D005978:Glutathione / Q000378:metabolism*; D006652:Histological Techniques; D007668:Kidney / Q000187:drug effects*; D008297:Male; D008647:Mesocricetus; D014018:Tissue Distribution
D018053:Arsenites; D005978:Glutathione; C015001:arsenite; D001151:Arsenic