Gene expression in distinct regions of the heart

Background Cytochrome P450 mono-oxygenases bring about metabolism of marry drugs, including verapamil, but no information is available on the metaboli sm of such drugs in the human heart. Methods We investigated the gene expression of major human cytochrome P450 monooxygenases in the various regions of explanted hearts from six patients with dilated cardiomyopathy and one with transposition of the arterial tru nk. For comparison we also studied samples of liver and lung from three pat ients and two samples of normal heart. The biological significance of tissu e-specific cytochrome monooxygenase gene expression was further investigate d by study of the microsomal metabolism of verapamil in ventricular tissue. Findings mRNA for the cytochromes 1A1, 2B6/7, 2C8-19, 2D6, and 4B1 was pred ominantly expressed in the right ventricle, the unilateral expression of th e 2D6 gene in right-venticular tissue is important because of its key role in the metabolism of beta-blockers. A strong correlation between tissue-spe cific gene expression and enzyme activity was found; microsomal metabolism of verapamil was confined to the right ventricle. By contrast, cytochrome P 450 3A genes (which are the major drug-metabolising enzymes in the liver an d the lung) were not expressed in any of the human heart tissues, and mRNA transcripts for epoxide hydrolase, cytochrome P450 2E1, and flavin-containi ng monooxygenases 2 and 5 were detected in all regions of the human heart a nd the great vessels. Interpretation These findings show that expression of genes for cytochrome P450 monooxygenases and verapamil metabolism are found predominantly in the right side of the heart. This finding may explain lack of efficacy of cert ain cardioselective drugs.