Effects of model traumatic injury on hepatic drug metabolism in the rat. V. Sulfation and acetylation.
A previously validated small mammal trauma model, hind-limb ischemia secondary to infrarenal aortic ligation in the rat, was utilized to investigate the effects of traumatic injury on sulfation and N-acetylation, two of the major phase II conjugative reactions of hepatic drug metabolism. Hepatic cytosolic sulfotransferase activity, as measured by several aryl and hydroxysteroid sulfation assays, was depressed by 20-29% after model injury. N-Acetyltransferase activity towards both isoniazid and p-aminobenzoic acid showed a similar 20-22% decrease. Moreover, as was previously observed with hepatic oxidative drug metabolism and with glucuronidation, the in vivo reactions of sulfation and acetylation were found to be significantly decreased by model trauma. In both cases, this effect on in vivo pharmacokinetics appeared to be correlated closely with trauma's influence on the conjugating enzymes, and relatively independent of the post-traumatic response of the necessary co-substrates. In vivo acetaminophen sulfation was depressed (24%) in parallel with hepatic sulfotransferase activity, despite an increased availability of sulfate for conjugation. Similarly, in vivo acetylation of isoniazid was diminished (23%) in conjunction with hepatic N-acetyltransferase activity, though hepatic acetyl-CoA content was elevated after model trauma. Thus, traumatic injury appears to have wide-ranging effects on a variety of determinants of hepatic drug metabolism.
Griffeth
L K
LK
Rosen
G M
GM
Rauckman
E J
EJ
D010129:4-Aminobenzoic Acid / Q000378:metabolism; D000082:Acetaminophen / Q000378:metabolism; D000105:Acetyl Coenzyme A / Q000378:metabolism; D000107:Acetylation; D000818:Animals; D001012:Aorta, Abdominal / Q000293:injuries; D001191:Arylamine N-Acetyltransferase / Q000378:metabolism; D002625:Chemistry, Organic; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D066298:In Vitro Techniques; D007538:Isoniazid / Q000378:metabolism; D007700:Kinetics; D008026:Ligation; D008297:Male; D055601:Organic Chemistry Phenomena; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D013431:Sulfates / Q000097:blood / Q000378:metabolism*; D013466:Sulfurtransferases / Q000378:metabolism; D014947:Wounds and Injuries / Q000201:enzymology / Q000378:metabolism*
D004364:Pharmaceutical Preparations; D013431:Sulfates; D000082:Acetaminophen; D000105:Acetyl Coenzyme A; D001191:Arylamine N-Acetyltransferase; D013466:Sulfurtransferases; D010129:4-Aminobenzoic Acid; D007538:Isoniazid