ABSTRACT:Cyp3A5 activity varies within any given ethnic population, suggesting that genetic variation within the Cyp3A5 gene may be the most important contributor to interindividual and interracial differences in Cyp3A-dependent drug clearance and response. The full extent of Cyp3A5 polymorphism in a white and an indigenous African population was analyzed using DNA direct sequencing procedures. The presence of 10 and 12 single nucleotide polymorphisms was detected in the white and African samples, respectively. Thirteen novel mutations occurring at low frequencies were identified in these populations. Significant differences were observed in the distribution of Cyp3A5*3, Cyp3A5*6, and Cyp3A5*7 alleles among white and African populations. The frequency of Cyp3A5*3 allele in white Canadians (ϳ93%) is higher than in Zimbabweans (77.6%) (p < 0.001). In contrast, Cyp3A5*6 and Cyp3A5*7 alleles are relatively frequent in African subjects (10-22%) but absent in white subjects (p < 0.001). These differences may reflect evolutionary pressures generated by environmental factors in geographically distinct regions. However, the genetic polymorphism of Cyp3A5 alone does not explain the interindividual differences in Cyp3A-mediated metabolism.

Abundant fat in the liver has been implicated in poor outcome after liver transplantation or liver surgery, but the reasons for this association are still unclear. The aim of the present study was to examine mechanisms that may be involved in hepatic dysfunction after ischemia-reperfusion (I/R) of the steatotic rat liver. Steatosis was produced by a choline-methionine-deficient (CMDD) diet. In the first experiment, isolated perfused rat livers, subjected to 24-hour cold storage followed by 120-minute reperfusion, were used to investigate hypothermic I/R injury of the steatotic rat liver. In the second experiment, livers were subjected to 60-minute partial left lobar vascular clamping to allow study of normothermic I/R injury. In the first experiment, compared with normal nonsteatotic liver, steatotic livers showed significantly greater injury, as assessed by amounts of hepatic enzymes released into the perfusate, bile production, the concentrations of reduced glutathione (GSH) in the perfusate, as well as in the livers themselves, and electron microscopic findings of sinusoidal microcirculatory injury. The addition of N-acetylcysteine (NAC), a precursor of glutathione, to the liver before cold storage significantly improved these parameters in steatotic livers. The second experiment showed that, compared with nonsteatotic livers, steatotic livers had lower concentrations of GSH and impaired rates of bile production. There was also evidence of increased oxidative stress in polymorphonuclear leukocytes (PMNLs) in liver or peripheral blood of rats with fatty livers. An anti-rat intercellular adhesion molecule-1 (ICAM-1) monoclonal antibody inhibited neutrophil infiltration into pericentral sinusoids and improved these parameters in the steatotic rats. We conclude that sinusoidal microcirculatory injury is involved in hypothermic I/R injury, that oxidative stress produced by PMNLs is involved in normothermic I/R injury, and that NAC and anti-rat ICAM-1 monoclonal antibody restore liver integrity in I/R injury.

The complete absence of Cyp3A5*3 allele and the accumulation of less than three copies of MDR-1 (T-129C, C3435T and G2677T) polymorphisms are associated with lower tacrolimus blood levels identifying these genotypes as markers for patients requiring higher tacrolimus doses.

In kidney transplant recipients, renal cell carcinoma (RCC) occurs either in the native kidney or, less frequently, in the grafted kidney. Here, we report a series of rare cases involving 5 patients from a single center who developed RCC in their grafts. The diagnosis was made serendipitously by ultrasound. The time lapse post-transplant varied from 4 to 17 years. Surgical treatment consisted of nephron-sparing surgery (NSS) in four cases and a secondary radical nephrectomy in one case. All tumors were less than 4 cm in diameter. The histopathology was clear cell type in four cases and papillary RCC in one case. Patients treated by NSS retained kidney function for 2 years or more, and none of them presented early neoplasia recurrence. In conclusion, NSS can be performed safely in grafted kidneys to treat incidental RCC. It prevents an immediate return to dialysis for patients.