Publications

OBJECTIVE

Peroxisome-proliferator-activated receptors gamma (PPAR gamma), is a key regulator of adipocyte differentiation and energy balance. Two naturally occurring mutations in the PPAR gamma gene, Pro115Gln and Pro12Ala, have recently been shown to impair the function of the PPAR gamma2 isoform of the receptor and to be associated with obesity or diabetes-related phenotypes in different populations.

SUBJECTS

We studied the occurrence and possible associations of the Pro115Gln and Pro12Ala in the PPAR gamma2 gene with several clinical and metabolic phenotypes in three independent large populations of non-obese non-diabetic, type 2 diabetic, and morbidly obese French Caucasians.

RESULTS

The Pro115Gln mutation was not found in any of the 1069 subjects screened including 626 obese patients. The frequency of the Pro12Ala mutation was similar in all groups (0.08, 0.11, 0.09) and was not associated with BMI or any of the clinical parameters tested.

CONCLUSIONS

We conclude that the Pro115Gln mutation is not a frequent cause of morbid obesity in Caucasians and that the Pro12Ala mutation is not associated with clinically significant changes in these populations.

Recently, we cloned a human organic cation transporter, hOCT1, which is expressed primarily in the liver. hOCT1 plays an important role in the cellular uptake and elimination of various xenobiotics including therapeutically important drugs. HIV protease inhibitors are a new class of therapeutic agents. The purpose of this study was to elucidate the interactions of HIV protease inhibitors with hOCT1 and to determine whether hOCT1 is involved in the elimination of these compounds. We studied the interactions of HIV protease inhibitors with hOCT1 in a transiently transfected human cell line, HeLa. Uptake studies were carried out 40 h post-transfection using the radiolabeled model organic cation, [(14)C]tetraethylammonium (TEA), under different experimental conditions. In cis-inhibition studies, all of the HIV protease inhibitors tested, i.e., indinavir (IC(50) of 62 microM), nelfinavir (IC(50) of 22 microM), ritonavir (IC(50) of 5.2 microM), and saquinavir (IC(50) of 8.3 microM) inhibited TEA uptake in HeLa cells expressing hOCT1. However, none of the HIV protease inhibitors trans-stimulated [(14)C]TEA uptake, suggesting that they are poorly translocated by hOCT1. Nelfinavir, ritonavir, and saquinavir demonstrated an apparent "trans-inhibition" effect. No enhanced uptake of [(14)C]saquinavir was observed in hOCT1 DNA-transfected cells versus empty vector-transfected cells. These data suggest that HIV protease inhibitors are potent inhibitors, but poor substrates, of hOCT1. Some HIV protease inhibitors may potently inhibit the uptake and elimination of cationic drugs that are substrates for hOCT1, leading to potential drug-drug interactions. Other transporters, e.g., MDR1 and MRP1, in HIV-targeted cells may control the intracellular concentrations of HIV protease inhibitors.