The effect of trans-stilbene oxide and other structurally related inducers of drug-metabolizing enzymes on glucuronidation.
Administration of trans-stilbene oxide, and new type of inducer of drug-metabolizing enzymes, to rats was found to increase hepatic microsomal UDP-glucuronyl transferase activity with both p-nitrophenol and chloramphenicol as substrate. In Triton X-100 activated microsomes the increase with p-nitrophenol as substrate was to approx. 250% of the control value, while the corresponding value for chloramphenicol was about 600%. These observations indicate that trans-stilbene oxide causes a mixed type 'induction' of UDP-glucuronyl transferase(s), i.e., changes in activity which resemble both those seen after induction with phenobarbital and after treatment with 3-methylcholanthrene. We have also shown that the activity of UDP-glucose dehydrogenase, the enzyme which produces UDP-glucuronic acid, is increased to about 300% of the control after administration of trans-stilbene oxide. The time course of this increase and of the return to control activity after cessation of treatment, the dose-response of this increase and the structural features of the trans-stilbene oxide molecule which are essential for the increase have all been examined. The other two enzymes involved in the conversion of glucose 6-phosphate to UDP-glucuronic acid, namely, phosphoglucomutase and UDP-glucose pyrophosphorylase, were found to be only slightly affected (a 30-60% increase) by treatment with trans-stilbene oxide. After induction with trans-stilbene oxide the hepatic level of UDP-glucuronic acid was unchanged.
D000818:Animals; D004790:Enzyme Induction / Q000187:drug effects*; D005965:Glucuronates / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000378:metabolism; D008297:Male; D006899:Mixed Function Oxygenases / Q000096:biosynthesis*; D010088:Oxidoreductases / Q000096:biosynthesis*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010733:Phosphoglucomutase / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013267:Stilbenes / Q000494:pharmacology*; D014533:Uridine Diphosphate Glucose Dehydrogenase / Q000378:metabolism
D005965:Glucuronates; D004364:Pharmaceutical Preparations; D011506:Proteins; D013267:Stilbenes; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; D014533:Uridine Diphosphate Glucose Dehydrogenase; D014453:Glucuronosyltransferase; D010733:Phosphoglucomutase; C025906:stilbene oxide