Toxicological Sciences, Vol 50, 82-89, Copyright © 1999 by Society of Toxicology
JM Peters, H Morishima, JM Ward, CJ Coakley, S Kimura and FJ Gonzalez
The mechanisms underlying phenacetin-induced toxicity and carcinogenicity
are not clear. In particular, it is not known whether these effects are
mediated by metabolic activation of the drug. CYP1A2 is known to metabolize
phenacetin in vitro. To determine the role of this enzyme in vivo, the
toxicity and carcinogenicity of phenacetin was examined in Cyp1a2-null mice
(that lack CYP1A2). Six- to 8-week-old wild type (+/+) or null (-/-) mice
were fed either a control diet, or one containing 1.25% phenacetin, ad
libitum for up to 67 weeks. Representative groups of mice were examined for
phenacetin-induced toxicity and carcinogenicity after 36, 48, 58, or 67
weeks of feeding. Consistent with the known role of CYP1A2 in phenacetin
metabolism, plasma levels of phenacetin were higher and acetaminophen
levels lower in the (-/-) mice fed phenacetin compared to phenacetin-fed
(+/+) controls. Weight gain was significantly depressed in both groups of
phenacetin-fed mice after 4 weeks of feeding, and continued to be lower for
the remainder of the experiment, compared to controls. Hepatomegaly and
splenomegaly were more severe in (-/-) mice but present in both genotypes
fed phenacetin at all time points assessed. Histological analysis of liver,
kidney, spleen, and urogenital tract also revealed a differential response
in the (-/-) mice fed phenacetin compared to (+/+) mice fed the same diet.
Further, mortality was the most severe in the (-/-) mice fed phenacetin
than in all other groups. Despite significant toxicity in (-/-) mice fed
phenacetin, only one renal carcinoma was found among them. Results from
this work demonstrate that, in the absence of CYP1A2, phenacetin is more
toxic than in controls. This provides evidence that metabolism of
phenacetin by CYP1A2 alters toxicity in vivo, and suggests that alternate
CYP1A2- independent metabolic pathways contribute to its toxicity.
ARTICLES
Role of CYP1A2 in the toxicity of long-term phenacetin feeding in mice
Laboratory of Metabolism, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. jpeters@helix.nih.gov
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