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.