Human kidney tubules detoxify chloroacetaldehyde, a presumed nephrotoxic metabolite of ifosfamide

The nephrotoxic effects of the antineoplastic drug ifosfamide have been att ributed to its hepatic metabolite chloroacetaldehyde. The effects of chloro acetaldehyde on isolated human kidney cortex tubules metabolizing lactate ( a physiologic substrate in human kidneys) were investigated. At concentrati ons of greater than or equal to0.5 mM, chloroacetaldehyde was toxic to the human kidney tubules, as demonstrated by a dramatic decrease in cellular AT P levels and a large increase in lactate dehydrogenase release; chloroaceta ldehyde also stimulated pyruvate accumulation and inhibited lactate removal and glucose synthesis. These effects, which were associated with incomplet e disappearance of chloroacetaldehyde and extensive depletion of the cellul ar CoA, acetyl-CoA, and glutathione contents, were prevented by the additio n of thiol-protecting drugs (mesna and amifostine). Human kidney tubules we re demonstrated to metabolize chloroacetaldehyde at high rates, presumably via aldehyde dehydrogenase, which is very active in human kidneys. Carbon-1 3 nuclear magnetic resonance spectroscopy measurements indicated that human kidney tubules converted [2-C-13]chloroacetaldehyde to [2-C-13]chloroadeta te, the further metabolism of which was very limited. At equimolar concentr ations, chloroacetate was much less toxic than chloroacetaldehyde, indicati ng that chloroacetate synthesis from chloroacetaldehyde by human kidney tub ules represents a detoxification mechanism that could play a role in vivo i n preventing or limiting the nephrotoxic effects observed during ifosfamide therapy.