The effects of adriamycin in vitro and in vivo on hepatic microsomal drug-metabolizing enzymes: Role of microsomal lipid peroxidation

Edward G. Mimnaugh, Michael A. Trush, Erika Ginsburg, Yoichiro Hirokata, Theodore E. Gram

Research output: Contribution to journalArticle

Abstract

The quinone-containing anticancer drug adriamycin augments the reduction of dioxygen to reactive oxygen species and thereby stimulates (sixfold) NADPH-dependent microsomal lipid peroxidation. In vitro the extensive adriamycin-promoted peroxidation depleted (85%) rat liver microsomal cytochrome P-450, severely inhibited cytochrome P-450-dependent monooxygenation (70%), and glucose-6-phosphatase activity (80%), and activated (450%) UDP-glucuronyltransferase activity. When lipid peroxidation was blocked by EDTA, adriamycin selectively decreased cytochrome P-450 and aminopyrine N-demethylase activity; NADPH-cytochrome c reductase, UDP-glucuronyltransferase, and glucose-6-phosphatase activities were unchanged. Washing and resedimenting peroxidized microsomes to remove adriamycin and soluble lipid peroxidation products failed to restore enzyme activities to control values. Adriamycin administered subacutely (5 mg/kg × three doses) to rats significantly descreased hepatic microsomal cytochrome P-450 content and reduced aminopyrine N-demethylase and NADPH-cytochrome c reductase activities compared to saline-treated controls. Microsomal lipid peroxidation was increased following the above adriamycin treatment. Thus, these data suggested that adriamycin was capable of impairing hepatic drug metabolism in vitro by stimulating membrane lipid peroxidation in a manner similar to carbon tetrachloride; the mechanism by which adriamycin treatment in vivo decreased the activity of the drug monooxygenase system remains unclear.

Original languageEnglish (US)
Pages (from-to)313-325
Number of pages13
JournalToxicology and Applied Pharmacology
Volume61
Issue number3
DOIs
StatePublished - 1981
Externally publishedYes

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Doxorubicin
Lipid Peroxidation
Lipids
Liver
Enzymes
Pharmaceutical Preparations
Cytochrome P-450 Enzyme System
Aminopyrine N-Demethylase
Glucose-6-Phosphatase
Glucuronosyltransferase
NADPH-Ferrihemoprotein Reductase
Uridine Diphosphate
Rats
Uridine Diphosphate Glucose
In Vitro Techniques
Carbon Tetrachloride
Enzyme activity
Membrane Lipids
Microsomes
Mixed Function Oxygenases

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

The effects of adriamycin in vitro and in vivo on hepatic microsomal drug-metabolizing enzymes : Role of microsomal lipid peroxidation. / Mimnaugh, Edward G.; Trush, Michael A.; Ginsburg, Erika; Hirokata, Yoichiro; Gram, Theodore E.

In: Toxicology and Applied Pharmacology, Vol. 61, No. 3, 1981, p. 313-325.

Research output: Contribution to journalArticle

Mimnaugh, Edward G. ; Trush, Michael A. ; Ginsburg, Erika ; Hirokata, Yoichiro ; Gram, Theodore E. / The effects of adriamycin in vitro and in vivo on hepatic microsomal drug-metabolizing enzymes : Role of microsomal lipid peroxidation. In: Toxicology and Applied Pharmacology. 1981 ; Vol. 61, No. 3. pp. 313-325.
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