Effects of cyclophosphamide and adriamycin on rat hepatic microsomal glucuronidation and lipid peroxidation.
The effect of cytotoxic drug administration, as a single dose i.p. to rats (six rats/treatment group), on hepatic microsomal UDP-glucuronosyltransferase (UGT) activity was investigated. Glucuronidation of morphine in microsomes from control rats apparently involved at least two enzymes. Administration of cyclophosphamide (CP; 200 mg/kg 7 days prior to killing) significantly increased the rate of morphine glucuronidation over the range 0.05-10 mM, and significantly increased the apparent Vmax for the high capacity isoenzyme from 1.25 +/- 0.12 to 1.95 +/- 0.39 nmol/mg/min. In contrast, the activity of 1-naphthol UGT was not significantly altered by administration of CP. Rats treated with the same dose of CP 1 day prior to killing showed a significant decrease in microsomal morphine-UGT activity at 0.05 and 2.5 mM morphine, but a significant increase in activity was observed following administration of CP or Adriamycin (AD; 10 mg/kg) 4 days prior to killing. The extent of microsomal lipid peroxidation was significantly increased in microsomes obtained from rats treated with CP or AD 4 days prior to killing, and was positively correlated (P less than 0.001) with the rate of glucuronidation of 0.05 and 2.5 mM morphine. Preincubation of microsomes in the presence of CP (5 mM) and AD (100 microM) significantly decreased the rate of glucuronidation of 2.5 mM morphine. In vitro NADPH-mediated lipid peroxidation significantly increased the activity of both the high and low affinity morphine-UGT isoenzymes. Administration of the cytotoxic drugs CP and AD may alter microsomal morphine-UGT activity via the process of lipid peroxidation, although other mechanisms cannot be excluded.
Lear
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School of Pharmacy, University of South Australia, Adelaide.
Nation
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RL
Stupans
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D000818:Animals; D003520:Cyclophosphamide / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology*; D005965:Glucuronates / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009020:Morphine / Q000378:metabolism; D009022:Morphine Derivatives / Q000032:analysis; D009249:NADP / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D005965:Glucuronates; D007527:Isoenzymes; D009022:Morphine Derivatives; D009249:NADP; D009020:Morphine; D004317:Doxorubicin; D003520:Cyclophosphamide; D014453:Glucuronosyltransferase; C018108:morphine-3-glucuronide