Von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome caused by germline mutations in the VHL gene. This gene, located in the 3p25-26 chromosome, is a tumor suppressor gene associated with the inhibition of angiogenesis and apoptosis, cell cycle exit, fibronectin matrix assembly, and proteolysis. To define the molecular basis of VHL in a Spanish population, we studied 33 patients suspected of suffering familial or de novo VHL disease and two familial pheochromocytoma cases. Sequence analysis of the coding regions of the VHL gene revealed germline sequence variants in 68.7% (24 out of 35) of the patients, and four of them presented with undescribed germline alterations: g.5429-5430insG, p.Leu128Arg, p.Tyr175Cys, and p.Tyr175Asn. For the remaining 11 patients who showed negative for point mutations, we performed Southern blot analysis and detected gross rearrangements in eight cases (22.8% of the index cases). Our results support the relevance of VHL gene analysis in familial pheochromocytoma cases and also in those with no familial history. In order to investigate the relevance of different amino acid changes in the VHL phenotype, we also analyzed the genotype-phenotype correlations using structural analysis to assess protein stability and complexes. The association of clear cell renal carcinoma (CCRC) development with a relatively high loss of structural stability in pVHL missense-mutants was consistent. Structural stability data in the genotype-phenotype correlations therefore provides us with a better understanding of VHL clinical implications. It is also a suitable approach to the evaluation of unknown significance changes.

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IntroductionOmeprazole is a benzimidazole derivative used as an antisecretory agent for the treatment of peptic acid disorders. It is metabolized by the cytochrome P-450 system in the liver. Like other imidazoles, omeprazole has the potential to inhibit the metabolism of some drugs by a competitive mechanism at the hepatic microsomal enzyme level [1]. It is now recognized that omeprazole interactions are confined to the limited number of drugs metabolized mainly by the cytochrome P-45011c subfamily [2]; it has been shown that this drug decreases phenytoin [3] and diazepam [4] metabolism but does not influence the disposition of drugs metabolized by other subfamilies within the cytochrome P-450 system, such as theophylline [5], propranolol [6] and ciclosporin [7].Studies of the interaction between omeprazole and warfarin have been performed but the results are controversial. Some studies suggest that omeprazole has little or no significant effect on the disposition of warfarin in healthy volunteers [8] or patients treated with anticoagulants [9]. Opposite to these, an increase in warfarin's effect has been reported in one patient after omeprazole addition [I0].Just like warfarin, acenocoumarol is a 3-substituted 4-hydroxycoumarin derivative and is the most commonly used oral anticoagulant in Europe. Acenocoumarol is a racemic mixture containing R(+) and S(-) enantiomers. As opposed to warfarin, the R(+) isomer of acenocoumarol is several times more potent as an anticoagulant than the S(-) enantiomer [I I]. At present, no interaction between omeprazole and acenocoumarol has been reported. We describe one case of potentiation of an acenocoumarol anticoagulant effect by omeprazole.

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