Effect of alpha-tocopherol on hepatic mixed function oxidases in hepatic ischemia/reperfusion.
This study was done to determine the relationship between microsomal lipid peroxidation during hepatic ischemia/reperfusion and alteration in cytochrome P-450-dependent drug metabolism. Rats were pretreated with alpha-tocopherol to inhibit lipid peroxidation or with vehicle (soybean oil) and then subjected to 60 min no-flow hepatic ischemia in vivo. Control animals were time-matched sham-ischemic animals. After 1, 5 or 24 hr of reperfusion, liver microsomes were isolated and cytochrome P-450 and mixed function oxidases were studied. In vehicle-treated ischemic rats, serum ALT levels peaked at 5 hr (5,242 +/- 682 U/L) and were significantly reduced by alpha-tocopherol pretreatment (1,854 +/- 229 U/L, p less than 0.01). Similarly, microsomal lipid peroxidation was elevated in the vehicle-treated ischemic group, but this elevation was prevented by alpha-tocopherol pretreatment. Microsomal cytochrome P-450 content and aminopyrine-N-demethylase activity were both decreased in vehicle-treated ischemic rats to 60% and 70% of sham-ischemic control levels, respectively. Although alpha-tocopherol restored cytochrome P-450 content to the level of sham-ischemic control rats, aminopyrine-N-demethylase activity remained at 76% of control with alpha-tocopherol treatment (p less than 0.01 compared with sham-ischemic control). In contrast to what was seen with cytochrome P-450 and aminopyrine-N-demethylase, aniline p-hydroxylase activity was elevated in the vehicle-treated ischemic rats compared with sham-ischemic control rats. These increases were prevented by alpha-tocopherol pretreatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Lee
S M
SM
Division of Pediatric Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Clemens
M G
MG
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D008054:Lipid Peroxides / Q000378:metabolism; D008099:Liver / Q000201:enzymology*; D008102:Liver Circulation; D008297:Male; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D015427:Reperfusion Injury / Q000201:enzymology*; D014810:Vitamin E / Q000494:pharmacology*
D008054:Lipid Peroxides; D014810:Vitamin E; D003577:Cytochrome P-450 Enzyme System; D000587:Oxidoreductases Acting on CH-NH Group Donors; C019668:amine oxidase, mixed function; D000410:Alanine Transaminase