Weak antioxidant capacity, particularly low catalase activity in the heart, may be a factor responsible for the high sensitivity of this organ to doxorubicin-induced oxidative damage. To test this hypothesis, a heart-specific promoter was used to drive the expression of murine catalase cDNA in transgenic mice. Fifteen healthy transgenic mouse lines were produced. Cardiac catalase activity was constitutively overexpressed in both atrium and ventricle, ranging from 2-to 630-fold higher than normal. This enzyme activity was not altered in liver, kidneys, lungs, and skeletal muscles. Other antioxidant components, including glutathione, glutathione peroxidase, glutathione reductase, metallothionein, and superoxide dismutase, were not altered in the catalaseoverexpressing heart. Mice (7 weeks old) from several transgenic lines and from nontransgenic controls were treated intraperitoneally with doxorubicin at a single dose of 20 mg/kg and sacrificed on the 4th day after treatment. As compared to normal controls, transgenic lines expressing catalase activity 60-or 100-fold higher than normal exhibited a significant resistance to doxorubicin-induced cardiac lipid peroxidation, elevation of serum creatine phosphokinase, and functional changes in the isolated atrium. Interestingly, 200-fold or greater elevation of catalase activity did not provide protection. The results provide direct evidence for the role of catalase in doxorubicin cardiotoxic responses.

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BackgroundThe secretion of organic solutes by the proximal tubules is an essential intrinsic kidney function. However, the clinical significance of the kidney’s clearance of tubular secretory solutes is uncertain.MethodsIn this prospective cohort study, we evaluated 3416 participants with CKD from the Chronic Renal Insufficiency Cohort (CRIC) study. We measured plasma and 24-hour urine concentrations of endogenous candidate secretory solutes at baseline, using targeted liquid chromatography–tandem mass spectrometry. The study defined CKD progression by a ≥50% decline in the eGFR, initiation of maintenance dialysis, or kidney transplantation. We used Cox proportional hazards regression to test associations of secretory-solute clearances with CKD progression and mortality, adjusting for eGFR, albuminuria, and other confounding characteristics.ResultsParticipants in this ancillary study had a mean age of 58 years and 41% were black; the median eGFR was 43 ml/min per 1.73 m2. After adjustment, lower kidney clearances of six solutes—kynurenic acid, pyridoxic acid, indoxyl sulfate, xanthosine, isovalerylglycine, and cinnamoylglycine—were associated with significantly greater risks of CKD progression, with clearance of kynurenic acid, a highly protein-bound solute, having the strongest association. Lower clearances of isovalerylglycine, tiglylglycine, hippurate, and trimethyluric acid were significantly associated with all-cause mortality after adjustment.ConclusionsWe found lower kidney clearances of endogenous secretory solutes to be associated with CKD progression and all-cause mortality, independent of eGFR and albuminuria. This suggests that tubular clearance of secretory solutes provides additional information about kidney health beyond measurements of glomerular function alone.

Purpose-The purpose is to determine absorption mechanism of five bioactive prenylated flavonoids (baohuoside I, icariin, epimedine A, B, and C) present in heat-processed Epimedium koreanum Nakai (Yin Yanghuo).Methods-Transport of five prenylated flavonoids present in heat-processed herbs were studied in the human intestinal Caco-2 model and the perfused rat intestinal model.Results-In the perfused rat intestinal model, prenylated flavonoids with a monoglucosidic bond (e.g., icariin) was rapidly hydrolyzed into corresponding metabolites (e.g., baohuoside I). In the Caco-2 model, apical to basolateral permeability of a monoglycoside baohuoside I (1.46 ×10 −6 cm/ sec) was more than 2 folds greater than four prenylated flavonoids with 2 or more sugar moieties (<0.6×10 −6 cm/sec). The slow apical to basolateral transport of baohuoside I was the result of efflux. This efflux was carrier-mediated and active since its transport was vectorial, concentration-and temperature-dependent with activation energies greater than 15 kcal/mol. Efflux of baohuoside I was significantly suppressed by inhibitors of BCRP and MRP2, whereas efflux of icariin was significantly inhibited only by p-glycoprotein inhibitor verapamil. Because YHH is often heat-processed for better efficacy, we determined and found the optimal condition for increasing contents of more bioavailable flavonoids (i.e., baohuoside I) to be 160-170°C for 5-7 min.Conclusions-Poor bioavailability of prenylated flavonoids results from their poor intrinsic permeation and transporter-mediated efflux. Heat processing parameters may be optimized to preserve the herb's bioavailable flavonoids, which help retain and improve its efficacy during processing.