title: Acyclovir-induced nephrotoxicity: the role of the acyclovir aldehyde metabolite.
abstract: For decades, acyclovir-induced nephrotoxicity was believed to be secondary to crystalluria. Clinical evidence of nephrotoxicity in the absence of crystalluria suggests that acyclovir induces direct insult to renal tubular cells. We postulated that acyclovir is metabolized by the alcohol dehydrogenase (ADH) enzyme to acyclovir aldehyde, which is metabolized by the aldehyde dehydrognase 2 (ALDH2) enzyme to 9-carboxymethoxymethylguanine (CMMG). We hypothesized that acyclovir aldehyde plays a role in acyclovir-induced nephrotoxicity. Human renal proximal tubular (HK-2) cells were used as our in vitro model. Western blot and enzymes activities assays were performed to determine whether the HK-2 cells express ADH and ALDH2 isozymes, respectively. Cytotoxicity (measured as a function of cell viability) assays were conducted to determine (1) whether the acyclovir aldehyde plays a role in acyclovir-induced nephrotoxicity and (2) whether CMMG induces cell death. A colorimetric assay was performed to determine whether acyclovir was metabolized to an aldehyde in vitro. Our results illustrated that (1) HK-2 cells express ADH and ALDH2 isozymes, (2) 4-methylpyrazole rendered significant protection against cell death, (3) CMMG does not induce cell death, and (4) acyclovir was metabolized to an aldehyde in tubular cells. These data indicate that acyclovir aldehyde is produced in HK-2 cells and that inhibition of its production by 4-methylpyrazole offers significant protection from cell death in vitro, suggesting that acyclovir aldehyde may cause the direct renal tubular insult associated with acyclovir.
authors: Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors: Patrina
authors: P
authors: Gunness
authors: Katarina
authors: K
authors: Aleksa
authors: John
authors: J
authors: Bend
authors: Gideon
authors: G
authors: Koren
mesh_terms: D000212:Acyclovir / Q000378:metabolism / Q000633:toxicity*; D000328:Adult; D000426:Alcohol Dehydrogenase / Q000378:metabolism; D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000447:Aldehydes / Q000633:toxicity; D000998:Antiviral Agents / Q000378:metabolism / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D000077604:Fomepizole; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D011720:Pyrazoles / Q000633:toxicity
chemical_list: D000447:Aldehydes; D000998:Antiviral Agents; D011720:Pyrazoles; D000077604:Fomepizole; D000426:Alcohol Dehydrogenase; D000444:Aldehyde Dehydrogenase; D000212:Acyclovir