Age-related changes in the mRNA levels of CYP1A1, CYP2B1/2 and CYP3A1 isoforms in rat small intestine.

It has been established beyond doubt that, as well as the liver, the small intestine is an important site of first-pass metabolism of numerous drugs, food components and toxic xenobiotics. However, there is not much information available about age-dependent changes of intestinal biotransformation pathways. In the present paper, we evaluated the relationships between intestinal cytochrome P450 complex activity and the age of animals. The study was carried out on male Sprague-Dawley rats (n = 5) from 5 age series: 0.5-, 2-, 4-, 20-, and 28 months old. Animals at every age series were divided into 4 groups: control and three groups of rats treated with the CYP450 specific inducers: phenobarbital, ß-naphtoflavone and dexamethasone, respectively. RNA was isolated from intestinal mucosa, and then standard RT-PCR was used for the analysis of CYP1A1, CYP2B1/2 and CYP3A1 mRNA expression. Additionally, the activities of NADPH-cytochrome P450 and NADH-cytochrome b(5) reductases in the microsomal fraction were biochemically estimated. The constitutive intestinal CYP1A1 mRNA expression changes during maturation and aging. Inducibility of CYP1A1 gene was evident in intestinal mucosa at 2-, 4- and 20-month-old rats. A similar pattern of changes was observed for CYP2B1/2 isoforms. CYP3A1 mRNA expression was not detected in small intestine of 2-week-old rats. In matured rats, constitutive intestinal CYP3A1 expression was low, although after induction, significant increases in CYP3A1 mRNA amount were noted in aged individuals. Intestinal activity of both analyzed reductases was lowest in immature rats and highest in 28-month-old animals. In conclusion, the activity of cytochrome P450 complex in rat small intestine was not decreased by the aging processes, so the high rate of oxidative metabolic reactions in intestinal mucosa can be maintained till the advanced life stage.

Diazoxide protects myocardial mitochondria, metabolism, and function during cardiac surgery: a double-blind randomized feasibility study of diazoxide-supplemented cardioplegia.

OBJECTIVES: The study was designed to assess whether diazoxide-mediated cardioprotection might be used in human subjects during cardiac surgery. METHODS: Forty patients undergoing coronary artery bypass grafting were randomized to receive intermittent warm blood antegrade cardioplegia supplemented with either diazoxide (100 micromol/L) or placebo (n = 20 in each group). Mitochondria were assessed before and after ischemia and reperfusion in myocardial biopsy specimens. Myocardial oxygen and glucose and lactic acid extraction ratios were measured before ischemia and in the first 20 minutes of reperfusion. Hemodynamic data were collected, and troponin I, creatine kinase-MB, and N-terminal prohormone brain natriuretic peptide levels were measured. All outcomes were analyzed by using mixed-effects modeling for repeated measures. RESULTS: No deaths, strokes, or infarcts were observed. Patients received, on average, 36.2 +/- 1.2 mg of diazoxide and 37.3 +/- 1.9 mg of placebo (P = .6). Diazoxide added to cardioplegia prevented mitochondrial swelling (8899 +/- 474 vs 9273 +/- 688 pixels before and after the procedure, respectively; P = .6) compared with that seen in the placebo group (8474 +/- 163 vs 11,357 +/- 759 pixels, P = .004). No oxygen debt was observed in the diazoxide group. Glucose consumption and lactic acid production returned to preischemic values faster in the diazoxide group. The following hemodynamic parameters differed between the diazoxide and placebo groups, respectively, in the postoperative period: cardiac index, 3.0 +/- 0.09 versus 2.6 +/- 0.09 L . min(-1) . m(-2) (P = .002); left cardiac work index, 2.81 +/- 0.07 versus 2.31 +/- 0.07 kg/m(2) (P < .001); oxygen delivery index, 420 +/- 14 versus 377 +/- 13 mL . min(-1) . m(-2) (P = .03); and oxygen extraction ratio, 29.3% +/- 1.1% versus 32.6% +/- 1.1% (P = .02). Postoperative myocardial enzyme levels did not differ, but N-terminal prohormone brain natriuretic peptide levels were lower in the diazoxide group (120 +/- 27 vs 192 +/- 29 pg/mL, P = .04). CONCLUSIONS: Supplementing blood cardioplegia with diazoxide is safe and improves myocardial protection during cardiac surgery, possibly through its influence on the mitochondria.

[Short stature in children with intrauterine growth retardation. New view of diagnostics and treatment]. / Niskoroslosc u dzieci z grupy wewnatrzmacicznego opóznionego wzrastania. Nowe spojrzenie na diagnostyke i leczenie.

One of the causes of short stature is IUGR. The body weight at the delivery of IUGR newborns is below 10th %ile compared to normal. The body weight at delivery is one of the factors influencing the final height of person. The height and the body weight of the children with low body weight at delivery is often much below normal during the first two years of their lives. Although more of them compensate this deficiency by the end of the second year of life, some of them are still affected and may never reach the genetically predicted height. The IUGR can be caused by the genetic and environmental factors, infection or fetal hypoxia. Avoiding the risk factors during pregnancy may prevent IUGR. IUGR affected children require special paediatric care and constant control of their growth and development. For the children with IUGR who did not catch-up their normal height there is a possibility to improve their final growth by GH therapy.