Gene expression in distinct regions of the heart

doi:10.1016/S0140-6736(00)99016-0

The Lancet

Volume 355, Issue 9208, 18 March 2000, Pages 979-983

https://doi.org/10.1016/S0140-6736(00)99016-0 Get rights and content

Summary

Background

Cytochrome P450 mono-oxygenases bring about metabolism of many drugs, including verapamil, but no information is available on the metabolism of such drugs in the human heart.

Methods

We investigated the gene expression of major human cytochrome P450 mono-oxygenases in the various regions of explanted hearts from six patients with dilated cardiomyopathy and one with transposition of the arterial trunk. For comparison we also studied samples of liver and lung from three patients and two samples of normal heart. The biological significance of tissue-specific cytochrome mono-oxygenase gene expression was further investigated by study of the microsomal metabolism of verapamil in ventricular tissue.

Findlngs

mRNA for the cytochromes 1A1, 2B6/7, 2C8-19, 2D6, and 4B1 was predominantly expressed in the right ventricle; the unilateral expression of the 2D6 gene in right-venticular tissue is important because of its key role in the metabolism of β-blockers. A strong correlation between tissue-specific gene expression and enzyme activity was found; microsomal metabolism of verapamil was confined to the right ventricle. By contrast, cytochrome P450 3A genes (which are the major drug-metabolising enzymes in the liver and the lung) were not expressed in any of the human heart tissue, and mRNA transcripts for epoxide hydrolase, cytochrome P450 2E1, and flavin-containing mono-oxygenases 2 and 5 were detected in all regions of the human heart and the great vessels.

Interpretation

These findings show that expression of genes for cytochrome P450 mono-oxygenases and verapamil metabolism are found predominantly in the right side of the heart. This finding may explain lack of efficacy of certain cardioselective drugs.

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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Early ReportGene expression in distinct regions of the heart

Summary

Background

Methods

Findlngs

Interpretation

Introduction

Section snippets

Production of complementary DNA

Gene expression studies

Discussion

Biochem Pharmacol

Am J Cardiol

Biochem Pharmacol

Anal Biochem

Biochem Pharmacol

J Biol Chem

Molecular genetics of the human cytochrome P450 monoxygenase superfamily.

Xenobiotica

Expression of extraherpatic cytochrome P450 in humans

Expression of cytochrome P450 3A enzymes in human lung: a combined RT-PCR and immunohistochemical analysis of normal tissue and lung tumours.

Arch Pharmacol

In vitro identification of the human cytochrome P450 enzymes involved in the metabolism of R(+) and S(-)-carvedilol.

Drug Metab Dispos

Early Report
Gene expression in distinct regions of the heart