Elsevier

Molecular Aspects of Medicine

Volume 24, Issues 4–5, August–October 2003, Pages 281-291
Molecular Aspects of Medicine

4-Hydroxynonenal as a bioactive marker of pathophysiological processes

https://doi.org/10.1016/S0098-2997(03)00023-2Get rights and content

Abstract

The review is focused on the currently major aspect of 4-hydroxynonenal (HNE) research––studies that combine biological activities of the aldehyde together with the methods of its identification in cells and tissues. Because there were some excellent reviews on HNE published in recent years, starting in 1990 and 1991 with supreme reviews done by Hermann Esterbauer, who discovered the aldehyde, and colleagues from the Institute of Biochemistry in Graz, this article pays most of attention to the most recent articles, published in the last 15 months. Additionally, an overview on the relevance of HNE is given with respect to the research and publication trends in the period of 10 years (1993–2002) according to the data in the Current Contents and Medline data bases.

It is obvious that HNE started in 1993 as a “toxic product of lipid peroxidation” and “second toxic messenger of free radicals”, to become in 2002 a reliable marker of oxidative stress, a possible causative agent of several diseases (such as Alzheimer’s disease), growth modulating factor and a signaling molecule. Novel analytical methods developed suitable pathways for HNE to become a clinically applicable marker of lipid peroxidation on one side and on the other a standardized parameter of food quality control. As it is also present physiologically in various cells and tissues, it is likely that HNE will soon become one of the most attractive factors for those who search for a small and reactive molecular link between genomics and proteomics.

Introduction

When we discussed our first joint results 10 years ago (Zarkovic et al., 1993), Hermann Esterbauer told me: “You should be careful, I am not sure that adding 0.1 or 1 μM HNE to cell culture medium really means that you treated cells with a physiological amount of HNE, especially when you have serum in the medium.” Our discussion led to the conclusion that most of biological activities we noticed were probably the consequence of direct interactions of HNE and bioactive peptides (proteins) in the cell culture medium that affected the growth of the cells in a manner different from plain serum growth factors. This assumption directed most of our further research in this field.

Nowadays, it is still an open question how much free HNE one could find in living systems (cells and organisms) to conclude what is the physiological level of HNE, while much of the aldehyde should be either metabolized or conjugated to amino acids (of course mostly bound on proteins and peptides, in particular glutathione). Esterbauer’s desire was to get information about the pathophysiological relevance of the aldehyde and its protein adducts. He believed that introducing immunohistochemistry would be the most suitable technical approach to the task. On the occasion of this special issue, I try to summarize how much was done on the pathway chosen by Esterbauer 10 years ago to define the role(s) of HNE in pathophysiology.

Section snippets

Ten years of HNE (1993–2002)

Many researchers working on oxidative stress would agree that HNE is one of the most challenging factors of oxidative stress. Since 1993 research interest in the molecule raised continuously (Fig. 1).

Increase of articles on HNE in 1997 was apparently due to Esterbauer’s death and the intention of many friends to publish articles in memory of him while the increase after 1998 is most likely due to three factors: (1) appearance of commercially available HNE, (2) development of the HNE-club and

Current situation

HNE is definitively becoming a marker of lipid peroxidation. Namely, as can be seen from Table 1, MEDLINE search recognizes 4-hydroxynonenal as keyword (678 articles in 10 years) related to lipid peroxidation and aldehydes (MDA), with specific enzymes, apoptosis and liver. HNE is also as frequent a key word as HNE (716 articles in 10 years) but is mostly affiliated with aldehydes, lipid peroxidation, neurons, vascular smooth muscle and enzyme inhibitors (the rest is confusion with Human

HNE as a bioactive marker of oxidative stress

During the period of 1993–2002 the idea of HNE as a marker of oxidative stress developed. Ten years ago HNE was mostly considered as one of the reactive aldehydes that act as a “second toxic messengers of free radicals” (Esterbauer et al., 1990, Esterbauer et al., 1991). Nowadays, HNE is still considered as “one of the major toxic products generated from lipid peroxides” (Mano et al., 2002), but also as “one of the most physiologically active lipid peroxides” (Kaneko et al., 2002), “one of

Methodological aspects

In the first 25 years of its history HNE was determined only by biochemical methods (chromatography). Probably the inability to determine it as simply as MDA was one of the reasons why MDA was and is still a more popular marker of lipid peroxidation than HNE. Nevertheless, there are still impressive efforts aimed to improve biochemical analysis of the content of HNE which will certainly increase quality of research in the field and give new research possibilities, such as work in plant

Food analysis

The last but not the least aspect of HNE detection is its presence in food due to fat oxidation. Not only should we seriously consider the possibility that the determination of HNE could become routine analysis for food quality control (even before clinical routine), but we have also to recognize the scientific relevance of studies in this field (Munasinghe et al., 2003).

Conclusions

Studies of HNE as a bioactive marker of oxidative stress may open a new arena in molecular biomedicine considering HNE as a small and highly reactive molecule that might link genomics and proteomics. Possible applications of HNE to modify pathophysiological processes and the use of substances “acting against it” (physiological and novel antioxidants) might not only increase our knowledge about oxidative stress and various diseases based on it but also develop into advanced adjuvant therapies.

Acknowledgments

This small review is dedicated to great people, those who are gone but who guide our work still, those who work with us and those at home who are proud of the work we do.

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