The effect of propylene glycol on the P450-dependent metabolism of acetaminophen and other chemicals in subcellular fractions of mouse liver.
Propylene glycol (PG) decreases the hepatotoxicity of acetaminophen (APAP). To elucidate the mechanism for this response, we measured the effect of PG on the in vitro metabolism of APAP by subcellular liver fractions from 6-10 week-old male B6C3F1 mice. The fractions were assayed for their ability to bioactivate APAP to N-acetyl-p-benzoquinone imine, which was trapped as APAP-glutathione conjugates or APAP-protein adducts, and for dimethyl-nitrosamine-N-demethylase (DMN), 4-nitrophenol hydroxylase (4-NPOH), and phenacetin-O-deethylase (PAD) activities. Activity in the crude mitochondrial-rich (10,000 x g pellet) fraction was low and PG had no effect. PG inhibited DMN and 4-NPOH, indicators of IIE1-dependent activity, and the formation of APAP-glutathione conjugates and APAP-protein adducts in both heavy (15,000 x g pellet) and light (100,000 x g pellet) microsomes. PAD, a measure of IA2-dependent activity, was not inhibited. These data demonstrate that PG selectively inhibits IIE1 activity, including the bioactivation of APAP, and implicates this as the mechanism for PG-mediated protection of APAP hepatotoxicity in mice.
Snawder
J E
JE
Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079.
Benson
R W
RW
Leakey
J E
JE
Roberts
D W
DW
D000082:Acetaminophen / Q000378:metabolism* / Q000493:pharmacokinetics; D000818:Animals; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D008099:Liver / Q000201:enzymology*; D008297:Male; D051379:Mice; D019946:Propylene Glycol; D011409:Propylene Glycols / Q000494:pharmacology*; D013347:Subcellular Fractions
D011409:Propylene Glycols; D000082:Acetaminophen; D019946:Propylene Glycol; D003577:Cytochrome P-450 Enzyme System