PMC

Correlation of plasma acetaminophen and alanine aminotransferase levels. Male GstP1/P2^(+/+) mice (n = 5) were treated with acetaminophen (300 mg/kg, i.p.), and plasma acetaminophen and ALT values were determined 5 h after dosing as detailed in Materials and Methods. Data were subject to a Pearson rank correlation test.

Liver histology in control mice compared with GstP null mice treated with a single oral dose of acetaminophen. Male GstP1/P2^(−/−) and GstP1/P2^(+/+) mice were treated with a single dose of acetaminophen 250 mg/kg body weight by gavage. At 24 and 48 h, the animals were killed and their livers removed, fixed, and sections (10 μm) cut and processed for staining with hematoxylin and eosin as detailed in Materials and Methods.

Plasma ALT levels in control and GstP null mice after treatment with acetaminophen. (A) Male GstP1/P2^(−/−) and GstP1/P2^(+/+) mice (n = 5) were treated with a single dose of acetaminophen (250 mg/kg body weight) by gavage, and plasma ALT values were determined as detailed in Materials and Methods. ■, GstP1/P2^(+/+); ○, GstP1/P2^(−/−). **, P < 0.01; * P < 0.05. (B) Male GstP1/P2^(−/−) and GstP1/P2^(+/+) mice (n = 5–10) were treated with a single i.p. dose of acetaminophen ranging from 100 to 350 mg/kg body weight, and plasma ALT values were determined as detailed in Materials and Methods. ■, GstP1/P2^(+/+); ○, GstP1/P2^(−/−). *, statistical difference between controls and nulls (***, P < 0.001).

Metabolism of acetaminophen in control and GstP null mice. Male GstP1/P2^(−/−) and GstP1/P2^(+/+) mice (n = 3) were treated with ³H-acetaminophen (4–7 μCi; 150 mg/kg in saline, 10 ml/kg), administered i.v. as a bolus over 2 min. Bile and urine were collected from these animals, and the level of acetaminophen metabolites was determined as detailed in Materials and Methods. Data are presented as a percentage of the radioactive dose excreted. (A) Urinary metabolites. (B) Biliary metabolites. Filled columns, GstP1/P2^(+/+); open columns, GstP1/P2^(−/−).

Hepatic glutathione levels in control and GstP null mice following treatment with a single dose of acetaminophen. Male GstP1/P2^(−/−) and GstP1/P2^(+/+) mice (n = 6) were treated with acetaminophen i.p. at a dose of 300 mg/kg, and hepatic reduced and oxidized glutathione content was determined as detailed in Materials and Methods. (A) Reduced glutathione; ■, GstP1/P2^(+/+); ○, GstP1/P2^(−/−); *, statistical difference between controls and nulls (*, P < 0.05, **, P < 0.005). (B) Oxidized:reduced glutathione ratio (GSSG:GSH). Filled columns, GstP1/P2^(+/+); open columns, GstP1/P2^(−/−); *, statistical difference between pre- and post-acetaminophen treatment in control animals (*, P < 0.01; **, P < 0.005).