Date of Award

2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Pharmaceutical and Chemical Sciences

First Advisor

Melanie Felmlee

First Committee Member

William K. Chan

Second Committee Member

David Thomas

Third Committee Member

Roshanak Rahimian

Fourth Committee Member

Doug Weiser

Abstract

Proton- and sodium-dependent monocarboxylate transporters (MCTs (SLC16A) and SMCTs (SLC5A)) transport monocarboxylates such as ketone bodies, lactate and pyruvate, as well as drugs such as gamma-hydroxybutyric acid. CD147 acts as an ancillary protein for MCT1 and MCT4, and is involved in membrane trafficking. Previously, it has been shown that MCT expression changes under different sex hormone conditions in skeletal muscle and Sertoli cells. However, it is unknown if MCTs, SMCTs or CD147 demonstrate sex differences in tissues where they play an important role in drug disposition. Monocarboxylate transporter substrates GHB and valproic acid have demonstrated sex differences in pharmacokinetic profiles. We hypothesize that sex hormones regulate monocarboxylate transporters and CD147 expression in drug disposition tissues, including the liver, intestine and kidney.

The purpose of the current study is to evaluate sex and sex hormone dependent regulation of MCT1, MCT4, SMCT1 and CD147 mRNA and protein expression in drug disposition tissues. Liver, kidney and intestinal segments (duodenum, jejunum and ileum) were harvested from estrus cycle staged female rats, ovariectomized (OVX) females, males and castrated (CST) male rats. Hormone replacement experiments were performed to investigate testosterone and 17β-estradiol dependent regulation of renal MCTs, SMCT1 and CD147 in OVX females and CST males. mRNA of MCT1, MCT4, SMCT1 and CD147 was evaluated by real time quantitative PCR. Whole cell protein and membrane protein was extracted, target protein expression was evaluated by western blot.

We have demonstrated sex and sex hormone dependent regulation of MCT1, MCT4, SMCT1 and CD147 in the liver, intestine regions and kidney occurs in a tissue specific manner. mRNA, protein expression and membrane localization of monocarboxylate transporters and CD147 were regulated differently by sex hormones. Sex differences in MCTs and SMCTs expression are important determinants of drug disposition in the body and sex differences in their regulation may contribute to differences in drug pharmacokinetics.

Pages

142

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