SLCO1B1 and ABCB1 variants synergistically influence the atorvastatin treatment response in South Indian coronary artery disease patients.

Introduction: Atorvastatin exhibits wide interindividual variability in treatment response, limiting the drug efficacy in coronary artery disease patients. Aim: To study the effect of genetic variants involved in atorvastatin transport/metabolism and correlate their lipid-lowering efficacy. Materials & methods: Genotyping was performed using 5'-hydrolysis probe method (n = 412), and the study evaluated the treatment response in 86 patients. Results: Significant reduction in total cholesterol and low-density lipoprotein cholesterol (LDL-C) were observed in SLCO1B1-rs4149056, rs4363657 and ABCB1-rs1045642 genotypes. The combined genotypes of ABCB1 and SLCO1B1 showed a strong synergistic effect in reducing the total cholesterol and LDL-C. Diabetes and smoking were observed to influence the LDL-C reduction. Conclusion: The genetic variants of SLCO1B1 and ABCB1 predict the lipid-lowering efficacy of atorvastatin, and this may be useful in genotype-guided statin therapy for coronary artery disease patients.

Indomethacin induces endoplasmic reticulum stress, but not apoptosis, in the rat kidney.

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used in clinical practice. However, their use is often associated with adverse effects in the gastrointestinal tract and kidney. Our earlier work with indomethacin, a prototype NSAID, has shown that it induced oxidative stress in the kidney in rats, an event that has been postulated to contribute to pathogenesis of its adverse effects in this organ. Endoplasmic reticulum (ER) stress responses have been shown to occur in response to oxidative stress. We investigated whether this occurred in the rat kidney, in response to indomethacin. For this, Wistar rats were orally gavaged with indomethacin (20mg/kg). Markers of ER stress were studied in the kidneys 1, 12 and 24h later. GRP78, p-PERK and nuclear sXBP-1, all markers of ER stress, were found to be increased in the rat kidney at 12h, in response to indomethacin; levels of these markers fell by 24h. The effects seen at 12h were attenuated by pre-treatment with zinc, a known anti-oxidant, which has earlier been shown to ameliorate indomethacin-induced oxidative stress. Activation of an ER stress response was not associated with induction of apoptosis, as measured by markers of apoptosis such as release of cytochrome c from mitochondria into the cytosol, activation of caspases 3 and 9, cleavage of poly-ADP ribose polymerase and the presence of DNA laddering. We conclude that indomethacin-induced oxidative stress activated ER stress, but did not lead to apoptosis in the rat kidney.

Indomethacin inhibits activation of endothelial nitric oxide synthase in the rat kidney: possible role of this effect in the pathogenesis of indomethacin-induced renal damage.

The clinical use of non-steroidal anti-inflammatory drugs (NSAIDs) is often associated with adverse effects in the kidney. Indomethacin, an NSAID that has been shown to induce oxidative stress in the kidney, was used to study the pathogenesis of renal damage induced by the drug in a rat model. Experimental animals were given indomethacin (20mg/kg) by oral gavage, sacrificed 1, 12 or 24h (h) later and the kidneys studied. Evidence of glomerular and tubular damage in the kidney was found in response to the drug. Renal tissue nitrite levels, a surrogate marker of nitric oxide (NO) synthesis, were significantly decreased at 12 and 24h. Indomethacin did not affect protein and mRNA levels of endothelial nitric oxide synthase (eNOS) or inducible NOS (iNOS). However, it significantly reduced the ratio of dimeric (active) to monomeric (inactive) eNOS in the kidney, 12 and 24h after drug administration. This was associated with reductions in heme content, both in renal tissue and in NOS. Heme oxygenase 1 (HO-1) mRNA (at 1 and 12h), protein (at 12 and 24h) and activity (at 1, 12 and 24h) were elevated in response to indomethacin. Nuclear translocation of Nrf2 (at 12h) and p38 MAPK signaling (at 12h and 24h), both of which are known to induce HO-1, also occurred in response to the drug. In summary, our results show that indomethacin reduced levels of activated eNOS in the kidney. This effect is possibly mediated by heme depletion, secondary to HO-1 induction that occurred downstream of Nrf2 and p38 MAPK signaling. We postulate that reduced renal eNOS activity may result in decreased NO levels, and hence reduced renal perfusion, leading to glomerular and tubular injury with subsequent renal damage.

Gestational and neonatal-onset hypothyroidism alters androgen receptor status in rat prostate glands at adulthood.

BACKGROUND: Infertility associated with congenital and early childhood hypothyroidism is an important reproductive health problem in men. Nevertheless, the exact mechanism underlying hypothyroidism-induced changes in the prostate gland, an androgen-dependent organ that contributes a significant portion of the seminal plasma remains obscure. The present study tested the hypothesis "transient gestational- or neonatal-onset hypothyroidism may have duration dependent and lobe specific effect on androgen receptor (AR) status in the prostate glands of adult rats." METHODS: Hypothyroidism was induced in pregnant and lactating rats by feeding 0.05% methimazole (MMI) through drinking water during fetal and neonatal milestones of testicular and prostatic development. Pregnant dams had MMI exposure from 9th day post-coitum (dpc) to 14 dpc (group II) or 21 dpc (group III). Lactating mothers had MMI exposure from day 1 post-partum (dpp) to 14 dpp (group IV) or up to 29 dpp (group V). AR status in the dorsolateral and ventral prostate lobes (DLP and VP) of the pups was assessed by RT-PCR, western blot and radio receptor assay. RESULTS: AR mRNA expression consistently decreased in the DLP of all groups, whereas it increased in VP of group III and V rats. AR protein consistently decreased in both DLP and VP of all experimental rats. AR nuclear ligand-binding activity diminished in groups II and IV, whereas it increased in groups III and V. CONCLUSION: The results obtained support the proposed hypothesis and indicate that an optimum thyroid activity during pre- and neonatal period determines AR status in the prostate glands at adulthood.