Effects of prochlorperazine on the function of integral membrane proteins.
We have studied the effects of prochlorperazine on the activities of UDP-glucuronosyltransferase and glucose-6-phosphatase (glucose-6-P'ase) in rat liver microsomes. The activity of UDP-glucuronosyltransferase was increased in a graded fashion by addition of prochlorperazine. Maximal stimulation occurred at 1 mg prochlorperazine to 2 mg microsomal protein, which resulted in a 6-fold increase in activity. However, with smaller concentrations of drug, there was a time-dependent increase in the activity of UDP-glucuronosyltransferase. Sensitivity of UDP-glucuronosyltransferase to activation by UDP-N-acetylglucosamine was lost after treatment of microsomes with prochlorperazine. These results indicate that prochlorperazine causes a profound reorganization of the interactions between lipids and enzyme since the activity and allosteric properties of UDP-glucuronosyltransferase are known to depend on interactions with lipids in a gel phase. Glucose-6-P'ase also was activated in a graded fashion by prochlorperazine; 1 mg of drug/2 mg microsomal protein resulted in a 60% increase in activity. The temperature-dependent instability of glucose-6-P'ase was increased by treatment of microsomes with prochlorperazine and could be prevented only partially by substrate. We conclude that prochlorperazine disrupts the structural organization between lipids and proteins in microsomal membranes, altering thereby the activity and regulation of at least two different integral membrane proteins.
Dannenberg
A
A
Department of Medicine, Cornell University Medical College, New York, NY 10021.
Zakim
D
D
D000818:Animals; D002462:Cell Membrane / Q000187:drug effects; D002746:Chlorpromazine / Q000494:pharmacology; D005952:Glucose-6-Phosphatase / Q000032:analysis*; D014453:Glucuronosyltransferase / Q000032:analysis*; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D011346:Prochlorperazine / Q000494:pharmacology*; D051381:Rats; D013997:Time Factors; D014268:Trifluoperazine / Q000494:pharmacology
D014268:Trifluoperazine; D014453:Glucuronosyltransferase; D005952:Glucose-6-Phosphatase; D002746:Chlorpromazine; D011346:Prochlorperazine