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.