Variations of malondialdehyde in pre-eclampsia

ABSTRACT

Malondialdehyde, as a biomarker of oxidative stress in pre-eclampsia, is discussed in terms of the determination methods, the validity of the obtained data, and variations in different studies, and it is concluded that there is a need for re-validation of the analytical methods and re-evaluation of its role as a biomarker of oxidative stress.

KEYWORDS:

• Eclampsia
• malondialdehyde
• oxidative stress

In a number of published papers (1–4), variations of malondialdehyde (MDA) as a biomarker of oxidative stress in healthy non-pregnant, healthy pregnant, and pre-eclamptic pregnant females were investigated. An imbalance between oxidants and anti-oxidants in pre-eclampsia could be shown using various pieces of evidence, and there is no doubt on the effects of oxidative stress in health/disease conditions; indeed, one can find lots of evidence in medical sources dealing with the effects of oxidative stress in pregnancy and pre-eclampsia. The major concern is “what is the best indicator of oxidative stress to be used in clinical investigations?” A number of biomarkers have been routinely used in the literature, including MDA, F₂-isoprostanes, vitamin A, vitamin C, vitamin E, carotenes, retinol, lipid hydroperoxides, protein carbonyl, total thiol, total antioxidant capacity, oxidized low density lipoprotein, paraoxonase 1, superoxide dismutase, glutathione peroxidase, catalase, uric acid, bilirubin, myeloperoxidase, reduced glutathione, leptin (5–10), and a multi-parameter term called total radical trapping antioxidant potential (TRAP), which represents the variations of serum urate, tocopherol, ascorbate, and total sulfhydryl groups in preeclampsia (11). The other biomarkers are not discussed in this communication, which focuses on MDA only.

The main critique is of the validity of MDA as a biomarker of oxidative stress. Concerning the characteristics of an ideal biomarker (for more details, see (19) and references therein), MDA fails to fulfill the requirements and we claim that it thus cannot be used as a reliable biomarker for oxidative stress in biomedical investigations. The aims of this communication are to provide some evidence to support our claim and to point out a number of technical problems associated with the production, consumption, and analysis of MDA in biological samples. In most of the clinical investigations published in medical journals, including recent works (1–4), simple spectrophotometric analysis (1) or liquid chromatographic analysis (2) of a thiobarbitoric acid (TBA) adduct of MDA as a biomarker of oxidative stress was carried out (19). Despite the wide applications of spectroscopic or chromatographic methods, there were insufficient validation data in the literature. From a practical viewpoint, an analytical method should be re-validated regarding the bioanalytical method validation criteria. Full details of these criteria can be found in bioanalysis textbooks and in the official website of the US Food and Drug Administration (13). In the published works, biological samples collected from case and control groups were analyzed and then statistically compared with each other. None of these works focused on the validity and repeatability of the MDA measurements, and there are some doubts on the validity of MDA measurement and its reliability as a biomarker of oxidative stress, which resulted in invalid and unreliable data.

MDA is constantly being generated in body fluids though various mechanisms and is continually removed by the endogenous antioxidant defense system. In addition to the technical points, MDA levels change with the circadian rhythm (14), which is another shortcoming in its role as an acceptable biomarker. To further support our hypothesis, we compared the MDA levels of healthy non-pregnant group from some available studies from a given university, i.e., Kahramanmaras Sutcu Imam University. Serum MDA levels of 8.7 nmol/mL (15), 2.20 ± 0.28 nmol/mL (16), 4.4 ± 0.5 nmol/mL (17) and 1900 ± 5300 nmol/mL (18) were found from the literature. It should be noted that the two latter works employed slightly different analytical conditions. Interestingly, the results reported in reference (18) are a thousand times higher that the values in other reports. A very high relative standard deviation, i.e. 279%, reveals that the variations among different samples analyzed by the same analytical method were high in the investigated healthy group (18). For this case, one may consider the possibility of a typographical or transcription error; however, similarly large discrepancies were also reported for healthy control groups in other investigations. As an example, the range of plasma MDA was 320–53,797 nmol/L (19). Different values were also reported for plasma samples; e.g. 6.54 ± 7.17 nmol/mL (20) and 2.92 ± 0.22 nmol/mL (21). Different serum MDA levels were also reported for healthy pregnant patients, for example: 2.95 ± 1.41 nmol/mL (4), 15.6 nmol/mL (15), and 7.89 ± 2.68 nmol/mL (22). Concerning that a single analytical method by Ohakawa et al. (12) was employed in a number of these studies (15, 16, 20, 21), variations were still high and could not be easily justified by the analytical method. There were also significant differences in MDA results reported for a single set of samples analyzed by a given research group (23–27). Further review of the literature on MDA and its production, stability, reaction with TBA and other biochemicals present in the biological samples, and the cross-reactivity of aldehydes and other compounds with TBA reveal that its determination with a simple spectrophotometric method could not provide valid analytical data for use in medical and clinical investigations. These points were comprehensively reviewed in a recent publication (19) and readers should refer to the review for further details. Beside the analytical problems of MDA, it is not a specific biomarker for pre-eclampsia and its levels could be affected by many other pathological conditions, such as Helicobacter pylori infection (28). It was also reported that most of the MDA measured using the TBA test is produced during the derivatization process at high temperature under acidic conditions and does not reflect the real MDA concentration in the biological sample (27). To reduce the variations of MDA levels owing to analytical methods, novel analytical techniques based on sensitive measurement of MDA using biosensors or lab-on-a-chip techniques may provide better results. This approach needs to be proved by further investigations in bioanalytical laboratories.

Considering that different MDA values were reported for healthy people employing a single analytical method, even by investigators at the same university, we conclude that using MDA as a valid biomarker of oxidative stress in clinical sciences should be re-investigated and interpretation of the present data on MDA levels in health and disease conditions may mislead research groups. Finally, the suitability of MDA as a biomarker of oxidative stress is questionable (25, 29, 30) and the clinical applications of this biomarker should be re-investigated by an expert panel of biochemists, bioanalysts, and clinical scientists.

Declaration of interest

The authors report no conflicts of interest.

Funding

The authors would like to thank Tabriz University of Medical Sciences for partial financial support and declare no conflict of interest.

Additional information

Funding

The authors would like to thank Tabriz University of Medical Sciences for partial financial support and declare no conflict of interest.