The temporal relationship between hepatic GSH loss, heme oxygenase induction, and cytochrome P450 loss following intraperitoneal aluminum administration to mice.
The time- and dose-dependent accumulation of aluminum (Al) in liver and its effect on several hepatic systems were investigated in female Swiss-Webster mice given intraperitoneal (ip) Al lactate. A single dose of 50, 75, or 100 mg Al/kg produced significant depletion of hepatic glutathione (GSH) and cytochrome P450 (P450) and an increase in heme oxygenase (HO) activity when measured at 6 hr. However, no increase in hepatic malondialdehyde (MDA) was seen at this time. Using a dose of 100 mg Al/kg, Al rapidly accumulated in liver (0.29 +/- 0.03 vs 0.12 +/- 0.04 micrograms Al/mg protein at 6 hr). Hepatic GSH was significantly depleted at 2, 4, and 6 hr postdosing, HO activity was significantly increased at 6, 12, 24, 48, and 96 hr postdosing, hepatic cytochrome P450 was decreased at 12, 18, 24, and 48 hr postdosing, while hepatic MDA was not significantly elevated until 24 hr postdosing. Twenty-four hours following three daily doses of 50 mg Al/kg, HO activity was increased, P450 levels were depleted, and hepatic Al content was significantly increased, although hepatic MDA was unaffected. We conclude that parenteral Al produces a course of hepatic damage that begins with GSH depletion and proceeds through a sustained increase in HO activity, with cytochrome P450 loss being an early event and production of hepatic MDA being a late event.
Fulton
B
B
Division of Nutritional Sciences, University of Illinois at Urbana-Champaign 61801.
Jeffery
E H
EH
D000535:Aluminum / Q000493:pharmacokinetics* / Q000633:toxicity*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000172:deficiency / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D005260:Female; D005978:Glutathione / Q000172:deficiency / Q000378:metabolism*; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis* / Q000187:drug effects; D007274:Injections, Intraperitoneal; D007773:Lactates / Q000008:administration & dosage; D019344:Lactic Acid; D008099:Liver / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism*; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000633:toxicity; D013997:Time Factors
D007773:Lactates; D017382:Reactive Oxygen Species; D019344:Lactic Acid; D008315:Malondialdehyde; D003577:Cytochrome P-450 Enzyme System; D000535:Aluminum; D006419:Heme Oxygenase (Decyclizing); D005978:Glutathione