CBR1 rs9024 genotype status impacts the bioactivation of loxoprofen in human liver

Loxoprofen is an anti‐inflammatory drug that requires bioactivation into the trans‐OH metabolite to exert pharmacological activity. Evidence suggests that carbonyl reductase 1 (CBR1) is important during the bioactivation of loxoprofen. This study examined the impact of the functional single nucleotide polymorphism CBR1 rs9024 on the bioactivation of loxoprofen in a collection of human liver samples. The synthesis ratios of trans‐OH loxoprofen/cis‐OH loxoprofen were 33% higher in liver cytosols from donors homozygous for the CBR1 rs9024 G allele in comparison with the ratios in samples from donors with heterozygous GA genotypes. Complementary studies examined the impact of CBR1 rs9024 on the bioactivation of loxoprofen in lymphoblastoid cell lines. CBR1 rs9024 genotype status impacts the synthesis of the bioactive trans‐OH metabolite of loxoprofen in human liver.     

Prediction of Human Brain Penetration of P-glycoprotein and Breast Cancer Resistance Protein Substrates Using In Vitro Transporter Studies and Animal Models

Four P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrates with human cerebrospinal fluid (CSF) concentrations and preclinical neuropharmacokinetics were used to assess in vitro–in vivo extrapolation of brain penetration in preclinical species and the ability to predict human brain penetration. Unbound brain (C_b,u), unbound plasma (C_p,u), and CSF compound concentrations (C_CSF) were measured in rats and nonhuman primates (NHPs), and the unbound partition coefficients (C_b,u/C_p,u and C_CSF/C_p,u) were used to assess brain penetration. The results indicated that for P-gp and BCRP dual substrates, brain penetration was severally impaired in all species. In comparison, for P-gp substrates that are weak or non-BCRP substrates, improved brain penetration was observed in NHPs and humans than in rats. Overall, NHP appears to be more predictive of human brain penetration for P-gp substrates with weak or no interaction with BCRP than rat. Although C_CSF does not quantitatively correspond to C_b,u for efflux transporter substrates, it is mostly within 3-fold higher of C_b,u in rat and NHP, suggesting that C_CSF can be used as a surrogate for C_b,u. Taken together, a holistic approach including both in vitro transporter and in vivo neuropharmacokinetics data enables a better estimation of human brain penetration of P-gp/BCRP substrates.     

A high frequency missense SULT1B1 allelic variant (L145V) selectively expressed in African descendants exhibits altered kinetic properties

1.?Human cytosolic sulfotransferase 1B1 (SULT1B1) sulfates small phenolic compounds and bioactivates polycyclic aromatic hydrocarbons. To date, no SULT1B1 allelic variants have been well-characterized.

2.?While cloning SULT1B1 from human endometrial specimens, an allelic variant resulting in valine instead of leucine at the 145th amino acid position (L145V) was detected. NCBI reported this alteration as the highest frequency SULT1B1 allelic variant.

3.?L145V frequency comprised 9% of 37 mixed-population human patients and was specific to African Americans with an allelic frequency of 25%. Structurally, replacement of leucine with valine potentially destabilizes a conserved helix (α8) that forms the “floor” of both the substrate and PAPS binding domains. This destabilization results in altered kinetic properties including a four-fold decrease in affinity for PAP (3′, 5′-diphosphoadenosine). K_ms for 3′-phosphoadenosine- 5′-phosphosulfate (PAPS) are similar; however, maximal turnover rate of the variant isoform (0.86?pmol/(min*μg)) is slower than wild-type (WT) SULT1B1 (1.26?pmol/(min*μg)). The L145V variant also displays altered kinetics toward small phenolic substrates, including a diminished p-nitrophenol K_m and increased susceptibility to 1-naphthol substrate inhibition.

4.?No significant correlation between genotype and prostate or colorectal cancer was observed in patients; however, the variant isoform could underlie specific pathologies in sub-Saharan African carriers.     

Plasmid-mediated doxycycline resistance in a Yersinia pestis strain isolated from a rat

The emergence of antibiotic-resistant Yersinia pestis strains represents a public health concern. Two antibiotic-resistant Y. pestis strains isolated from Madagascar have been previously identified and characterised. Both strains carried conjugative plasmids that conferred resistance to streptomycin or to multiple antibacterial drugs, respectively. Here we characterised a novel Y. pestis strain (IP2180H) that exhibited resistance to doxycycline. This strain was isolated from a rat in Antananarivo (Madagascar) in 1998. Resistance was carried by a conjugative plasmid (pIP2180H) homologous to pB71 from Salmonella enterica. The plasmid of the previously identified streptomycin-resistant Y. pestis strain was also sequenced and it was found that the three antibiotic resistance Y. pestis plasmids sequenced until now are genetically unrelated and are also unrelated to multidrug resistance plasmids from the phylogenetically close bacterial species Yersinia pseudotuberculosis. The fact that the three antibiotic-resistant Malagasy Y. pestis strains were isolated from different hosts, at different times, from distant locations, and carried unrelated plasmids indicates independent horizontal acquisition of genetic material and further demonstrates the capacity of Y. pestis to acquire antibiotic resistance plasmids under natural conditions. Since these resistance plasmids can frequently carry or easily trap antibiotic resistance cassettes, the emergence of new multidrug-resistant Y. pestis strains may be expected and would represent a major health threat.     

Loratadine augments emotional blushing

The aim of this study was to determine whether loratadine, a selective inverse agonist of peripheral histamine H₁ receptors, would reduce emotional blushing. Loratadine (10?mg) or placebo was administered orally one hour before 31 healthy participants sang a children's nursery rhyme to evoke embarrassment and blushing. Skin blood flow was monitored via a laser Doppler probe attached to the cheek. Increases in facial blood flow while participants sang were greater in the loratadine than the placebo group (mean increase?±?standard deviation 71?±?52% in the loratadine group versus 35?±?37%, p?=?.036). However, perceptions of blushing were similar in both groups. These findings suggest that loratadine augmented blushing rather than inhibiting it. Thus, histamine released during blushing may inhibit acute increases in facial blood flow by evoking H₁ receptor-mediated vasoconstriction.     

丹酚酸B调控pSmad3C/pSmad3L发挥抗肝纤维化-肝细胞癌作用

目的观察丹酚酸B(salvianolic acid B,Sal B)对二乙基亚硝胺(diethylnitrosamine,DEN)诱导小鼠肝纤维化-肝细胞癌进程的影响,并探讨Sal B经由p Smad3C/p21介导的抑癌信号、p Smd3L/PAI-1/c-Myc介导的促肝纤维化-肝癌信号转换机制。方法昆明种♂小鼠100只,随机分组,DEN诱导小鼠肝纤维化-肝细胞癌模型,不同剂量Sal B(15、30mg·kg^-1·d^-1,ig)及阳性药秋水仙碱(0.2 mg·kg^-1·d^-1,ig)干预。于造模第12周、第16周分批处死小鼠,肝脏活检,苏木精-伊红(HE)染色、Van Gieson(VG)染色观察肝组织病理学特征,Western blot法检测肝组织中p Smad3C、p S-mad3L、p21、纤溶酶原激活物抑制剂-1(plasminogen activator inhibitor 1,PAI-1)及c-Myc蛋白表达。结果正常组肝脏表面光滑、质地柔软,模型组第12周时肝脏表面粗糙、质地变硬,第16周时肝脏表面可见弥漫性结节、质地坚硬;而丹酚酸B干预组以上病变明显改善。HE及VG染色显示,正常组肝组织结构正常,模型组第12周时肝组织炎细胞浸润、胶原纤维增生,形成假小叶结构;第16周时肝小叶结构紊乱,细胞核变大、分裂相增多、异型性明显;Sal B干预组肝组织病变程度明显减轻。Western blot结果显示,正常组肝组织中p Smad3C、p Smad3L、PAI-1表达均较少,p21、c-Myc几乎不表达;模型组第12周时肝组织中p Smad3C无明显变化,p S-mad3L、PAI-1、p21表达增多,第16周时p Smad3C、p Smad3L、p21、PAI-1、c-Myc表达皆有增加;而Sal B干预组第12周时p Smad3C、p21表达明显增加,p Smad3L、PAI-1蛋白水平明显降低,第16周时p Smad3C表达明显增加,p21几乎无变化,p Smad3L、PAI-1、c-Myc表达明显降低。结论Sal B延缓DEN诱导的小鼠肝纤维化-肝细胞癌进程,其机制可能与调控p Smad3C/p21、p Smad3L/PAI-1/c-Myc信号转换有关。