Early ReportGene expression in distinct regions of the heart
Introduction
Many drugs and xenobiotics are metabolised by oxidation catalysed by cytochrome P450 enzymes.1 The main site of degradation is the liver, but lung and various sections of the gut2, 3 are secondary sites of metabolism. Little is known about the metabolic capacity of the human heart. β-blockers, calcium antagonists, inhibitors of angiotensin-converting enzyme (ACE) and ACE-receptor antagonists are all metabolised via cytochrome-P450-dependent pathways.4, 5, 6, 7
Rapid removal of durgs from the blood can result in inefficient pharamacotherapy. For unknown reasons drug therapy of right-ventricular hypertrophy is not successful in some cases,8, 9 such failure may be a result of metabolic inactivation.
We investigated the gene expression of major cytochrome P450 mono-oxygenases, flavin-containing mono-oxygenases, and epoxide hydrolase in distinct regions of the human heart. We also studied the relation between tissue-specific gene expression and metabolism of verapamil in ventricular tissue.
Section snippets
Production of complementary DNA
Approval was obtained from the ethics committee of the Medical School of Hannover. We examined seven explanted human hearts and for comparison three tissue samples from liver and lung. Immediately after explantation, tissue pieces were removed from the left and right ventricles, left and right atria, and pulmonary artery, the ascending aorta, and the ventricular septum. Excised tissue was immediately shock-frozen in liquid nitrogen and stored at -80%C until analysis.
Total RNA was isolated from
Gene expression studies
Characteristics of the seven patients are summarised in table 1. Most patients showed expression of all genes (except cytochromes P450 4B1 and 2F1) in lung and liver tissue (figure 1). Cytochrome P450 4B1 was not expressed in liver but was restricted to the right side of the heart and the pulmonary circulation (table 2). Cytochrome P450 1A1 mRNA was also predominantly expressed in the pulmonary artery, the right-ventricular tissue, and the ascending aorta as well as in lung and liver. By
Discussion
We found that expression of cytochrome P450 genes 1A1, 2B6/7, 2C8 19, 2D6, and 4B1 in the heart was predominant in the right ventricle. The expression of the cytochrome P450 2D6 gene in right ventricle is particularly relevant to pharmacotherapy, because of the key role of this enzyme in the metabolism of β-blockers.14 The finding that verapamil was metabolised only by microsomes prepared from the right ventricle extends the gene-expression data to functional activity of the translated
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