The inhibitory effect of antiretroviral drugs on the L-carnitine uptake in human placenta

The aim of the study is to evaluate the utility of cystatin C (Cys C) determination in monitoring of HIV seropositive patients, based on recent literature concerning clinical investigation. Determination of serum CysC concentration can be helpful in monitoring the kidney function and eGFR (estimated GFR) calculation, however infection and inflammation markers influence should be included. A risk assessment of the appearance of cardiovascular incidents and risks of the all-cause mortality can be the other application for this parameter. The urinary CysC concentration can serve as the diagnostic marker of kidney tubular injuries triggered with adverse effects of antiretroviral drugs eg. tenofovir. In order to introduce applications into the routine clinical practice, further research is essential. Research concerning antiviral activity of cystatin C suggest, that CysC suppresses the viral replication due to inhibition of HIV protease, but in some cases its inhibitory effect on cathepsin B may be harmful and cause progression of the infection. In order that CysC could effectively use in the future, further experiments are needed to evaluate its effect on all sort virus strains, both dependent and independent of CD4+ T-lymphocytes, strains of the HIV virus.

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Inhibitory effect of fluoride on insulin receptor autophosphorylation and tyrosine kinase activity

Biochemical Journal ◽

10.1042/bj2910615 ◽

1993 ◽

Vol 291 (2) ◽

pp. 615-622 ◽

Cited By ~ 8

Author(s):

F Viñals ◽

X Testar ◽

M Palacín ◽

A Zorzano

Keyword(s):

Tyrosine Kinase ◽

Insulin Receptor ◽

Binding Site ◽

Human Placenta ◽

Kinase Activity ◽

Insulin Receptors ◽

Inhibitory Effect ◽

Beta Subunit ◽

Tyrosine Kinase Activity ◽

Tyrosine Residues

Fluoride is a nucleophilic reagent which has been reported to inhibit a variety of different enzymes such as esterases, asymmetrical hydrolases and phosphatases. In this report, we demonstrate that fluoride inhibits tyrosine kinase activity of insulin receptors partially purified from rat skeletal muscle and human placenta. Fluoride inhibited in a similar dose-dependent manner both beta-subunit autophosphorylation and tyrosine kinase activity for exogenous substrates. This inhibitory effect of fluoride was not due to the formation of complexes with aluminum and took place in the absence of modifications of insulin-binding properties of the insulin receptor. Fluoride did not complete with the binding site for ATP or Mn2+. Fluoride also inhibited the autophosphorylation and tyrosine kinase activity of receptors for insulin-like growth factor I from human placenta. Addition of fluoride to the pre-phosphorylated insulin receptor produced a slow (time range of minutes) inhibition of receptor kinase activity. Furthermore, fluoride inhibited tyrosine kinase activity in the absence of changes in the phosphorylation of prephosphorylated insulin receptors, and the sensitivity to fluoride was similar to the sensitivity of the unphosphorylated insulin receptor. The effect of fluoride-on tyrosine kinase activity was markedly decreased when insulin receptors were preincubated with the copolymer of glutamate/tyrosine. Prior exposure of receptors to free tyrosine or phosphotyrosine also prevented the inhibitory effect of fluoride. However, the protective effect of tyrosine or phosphotyrosine was maximal at low concentrations, suggesting the interaction of these compounds with the receptor itself rather than with fluoride. These data suggest: (i) that fluoride interacts directly and slowly with the insulin receptor, which causes inhibition of its phosphotransferase activity; (ii) that the binding site of fluoride is not structurally modified by receptor phosphorylation; and (iii) based on the fact that fluoride inhibits phosphotransferase activity in the absence of alterations in the binding of ATP, Mn2+ or insulin, we speculate that fluoride binding might affect the transfer of phosphate from ATP to the tyrosine residues of the beta-subunit of the insulin receptor and to the tyrosine residues of exogenous substrates.

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Comparative Study of the Effects of Antituberculosis Drugs and Antiretroviral Drugs on Cytochrome P450 3A4 and P-Glycoprotein

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02278-13 ◽

2014 ◽

Vol 58 (6) ◽

pp. 3168-3176 ◽

Cited By ~ 13

Author(s):

Yasuhiro Horita ◽

Norio Doi

Keyword(s):

Cytochrome P450 ◽

Mdck Cells ◽

Inhibitory Effect ◽

Antiretroviral Drugs ◽

Aminosalicylic Acid ◽

P Glycoprotein ◽

Heparg Cells ◽

Group 5 ◽

Almost All

ABSTRACTPredicting drug-drug interactions (DDIs) related to cytochrome P450 (CYP), such as CYP3A4 and one of the major drug transporters, P-glycoprotein (P-gp), is crucial in the development of future chemotherapeutic regimens to treat tuberculosis (TB) and TB/AIDS coinfection cases. We evaluated the effects of 30 anti-TB drugs, novel candidates, macrolides, and representative antiretroviral drugs on human CYP3A4 activity using a commercially available screening kit for CYP3A4 inhibitors and a human hepatocyte, HepaRG. Moreover, in order to estimate the interactions of these drugs with human P-gp, screening for substrates was performed. For some substrates, P-gp inhibition tests were carried out using P-gp-expressing MDCK cells. As a result, almost all the compounds showed the expected effects on human CYP3A4 both in thein vitroscreening and in HepaRG cells. Importantly, the unproven mechanisms of DDIs caused by WHO group 5 drugs, thioamides, andp-aminosalicylic acid were elucidated. Intriguingly, clofazimine (CFZ) exhibited weak inductive effects on CYP3A4 at >0.25 μM in HepaRG cells, while an inhibitory effect was observed at 1.69 μM in thein vitroscreening, suggesting that CFZ autoinduces CYP3A4 in the human liver. Our method, based on one of the pharmacokinetics parameters in humans, provides more practical information associated with not only DDIs but also with drug metabolism.

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