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Allosteric Enzyme- and Transporter-Based Interactions

  • Murali Subramanian
  • Timothy S. Tracy
Chapter

Abstract

Allosterism in enzymes and transporters can result in alterations in kinetic profiles and in rates of metabolism and transport. Cooperativity due to allosteric interactions has been observed with drug-metabolizing enzymes such as the cytochromes P450 and the uridine glucuronosyltransferases. In addition, transporters such as P-glycoprotein and breast cancer resistance protein have been demonstrated to also exhibit allosteric interactions resulting in cooperativity. Kinetic profiles such as autoactivation (sigmoidal profile), biphasic and substrate inhibition have been observed to occur due to homotropic cooperativity, and heteroactivation has been observed to occur due to heterocooperativity. Numerous examples of all types of allosteric interactions have been observed in vitro but in vivo examples are limited. The correct kinetic equation should be applied to kinetic profiles to properly estimate kinetic parameters for use in in vitro–in vivo correlations.

Keywords

Substrate Inhibition Breast Cancer Resistance Protein Kinetic Profile Allosteric Interaction Biphasic Kinetic 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

P450 s

Cytochrome P450 s

UGT s

UDP-glucuronosyltransferases

SULT s

sulfotransferases

P-gp

P-glycoprotein

CBZ

carbamazepine

CBZ-E

carbamazepine–epoxide

DHEA

dehydroepiandrosterone

UDPGA

uridine diphosphate glucuronic acid

PhIP

2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine

MDCK-MDR

Madin Darby canine kidney-multiple drug resistance

BCRP

breast cancer resistance protein

HLMs

human liver microsomes

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© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of Experimental and Clinical PharmacologyUniversity of MinnesotaMinneapolisUSA
  2. 2.Department of Experimental and Clinical PharmacologyCollege of Pharmacy, University of MinnesotaMinneapolisUSA

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