2019-07-21
Lipid peroxidation and antioxidant status in blood of patients with uterine myoma, endometrial polypus, hyperplastic and malignant endometrium; PY2006;Vinca Institute of Nuclear Sciences;Serbia (塞爾維亞);_WJD_2019-0721_
Source (資訊來源):
https://scielo.conicyt.cl/scielo.php?script=sci_arttext&pid=S0716-97602006000500005
Info cited on 2019-07-21-WD7 (資訊引用於 中華民國108年7月21日) by 湯偉晉 (WeiJin Tang)
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Biological Research
versión impresa ISSN 0716-9760
Biol. Res. v.39 n.4 Santiago 2006
http://dx.doi.org/10.4067/S0716-97602006000500005
BiolRes 39: 619-629, 2006
Lipid peroxidation and antioxidant status in blood of patients with uterine myoma, endometrial polypus, hyperplastic and malignant endometrium
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子宮肌瘤，子宮內膜息肉，增生和惡性子宮內膜患者血液中脂質過氧化和抗氧化狀態
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SNEZANA PEJIC, JELENA KASAPOVIC, ANA TODOROVIC, VESNA STOJILJKOVIC, and SNEZANA B. PAJOVIC
Laboratory of Molecular Biology and Endocrinology, Vinca Institute of Nuclear Sciences, Belgrade, Serbia (塞爾維亞)
ABSTRACT
Oxidative stress is considered to be involved in pathogenesis of many disorders of the female genital tract. In this study, we explored the lipid peroxidation levels and antioxidant enzyme activities in women diagnosed with different forms of uterine diseases in order to evaluate the extent of oxidative stress in blood of such patients. Blood samples of healthy subjects and gynecological patients were collected and subjected to assays for superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and lipid hydroperoxides. The results show that alterations of measured parameters vary with the enzyme type and diagnosis. However, both reduction in antioxidants and elevation of lipid peroxidation were observed in general. Lipid hydroperoxides level was negatively correlated to superoxide dismutase and glutathione peroxidase activities, as well as positively correlated to catalase activity. In addition, the lipid hydroperoxides/ glutathione peroxidase ratio was found to be increased, according to the type of uterine disease. The obtained results show that perturbation of antioxidant status is more pronounced in blood of patients with premalignant (hyperplastic) and malignant (adenocarcinoma) lesions, compared to those with benign uterine changes such as polypus and myoma.
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抽象
氧化應激被認為涉及許多女性生殖道疾病的發病機理。在這項研究中，我們探討了被診斷患有不同形式子宮疾病的女性的脂質過氧化水平和抗氧化酶活性，以評估這些患者血液中氧化應激的程度。收集健康受試者和婦科患者的血液樣品，並進行超氧化物歧化酶，過氧化氫酶，穀胱甘肽過氧化物酶，穀胱甘肽還原酶和脂質氫過氧化物的測定。結果表明，測量參數的變化隨酶類型和診斷而變化。然而，通常觀察到抗氧化劑的減少和脂質過氧化的升高。脂質氫過氧化物水平與超氧化物歧化酶和穀胱甘肽過氧化物酶活性呈負相關，並且與過氧化氫酶活性呈正相關。此外，根據子宮疾病的類型，發現脂質氫過氧化物/穀胱甘肽過氧化物酶比率增加。獲得的結果表明，與具有良性子宮變化的患者（例如息肉和肌瘤）相比，具有癌前（增生）和惡性（腺癌）病變的患者的血液中抗氧化狀態的擾動更明顯。
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Key terms: antioxidant enzymes, endometrial polypus, endometrial hyperplasia, endometrial adenocarcinoma, lipid peroxidation, uterine myoma,
INTRODUCTION
It is widely accepted that excess production of free radicals, particularly oxygen radicals, creates a condition known as oxidative stress, which causes cell damage and plays fundamental role in various diseases, aging and neoplastic transformation (Sun, 1990; Halliwell, 1996). Also, by-products of lipid peroxidation perturb structural organization and functions of the cell membrane, consequently leading to cell destruction (Porter et al., 1995; Spiteller, 2003). Deleterious effects of reactive oxygen species (ROS) and lipid peroxidation (LPO) products are counteracted by the antioxidative defense system (AOS), which consists of nonenzymatic antioxidant molecules such as tocopherol, carotenoids, ascorbate, glutathione (Briviba and Sies, 1994) and the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reducíase (GR), and glutathione transferase (GST). SOD, the first line of defense against oxygen free radicals, catalyzes dismutation of superoxide anion radical into hydrogen peroxide (H202), which can be transformed into water and oxygen by CAT or GPx. Besides hydrogen peroxide, GPx also reduces lipid or nonlipid hydroperoxides while oxidizing glutathione (GSH). The oxidized GSH is then reduced by GR (Yu, 1994). Antioxidants show different patterns during neoplastic transformation and tumor cells exhibit high variability of antioxidant enzymes (AOE) activities, when compared to their appropriate normal cell counterparts (Sun, 1990).
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介紹
人們普遍認為，過量產生的自由基，尤其是氧自由基，會產生一種稱為氧化應激的狀態，這種狀況會導致細胞損傷，並在各種疾病，衰老和腫瘤轉化過程中發揮重要作用（Sun，1990; Halliwell，1996）。此外，脂質過氧化的副產物擾亂細胞膜的結構組織和功能，從而導致細胞破壞（Porter等，1995; Spiteller，2003）。抗氧化防禦系統（AOS）抵消了活性氧（ROS）和脂質過氧化（LPO）產物的有害影響，其由非酶抗氧化分子如生育酚，類胡蘿蔔素，抗壞血酸，穀胱甘肽（Briviba和Sies，1994）和抗氧化酶超氧化物歧化酶（SOD），過氧化氫酶（CAT），穀胱甘肽過氧化物酶（GPx），穀胱甘肽還原酶（GR）和穀胱甘肽轉移酶（GST）。 SOD是抗氧自由基的第一道防線，催化超氧陰離子自由基歧化成過氧化氫（H2O2），可通過CAT或GPx轉化為水和氧。除過氧化氫外，GPx還可以還原脂質或非脂質氫過氧化物，同時氧化穀胱甘肽（GSH）。然後通過GR還原氧化的GSH（Yu，1994）。抗氧化劑在腫瘤轉化過程中表現出不同的模式，與其適當的正常細胞對應物相比，腫瘤細胞表現出高度的抗氧化酶（AOE）活性變異性（Sun，1990）。
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Although endometrial hyperplasia is regarded as a preliminary stage of endometrioid carcinomas (Hammond and Johnson, 2004), there is a lack of data on the relationship between oxidative stress and antioxidant enzymes in such patients. Some investigations so far have revealed elevated levels of lipid peroxidation and perturbed AOE activities in peripheral circulation and tissues of women with benign and malign diagnosis. Chiou and Hu (1999) reported lowered plasma and erythrocytes SOD activity of both uterine cervicitis and myoma patients, while the activities of CAT and GPx were elevated in cervicitis patients and lowered in myoma patients. Similar observations on erythrocytes SOD, CAT and GPx activities of cervicitis patients were made by Manoharan et al. (2004), whereas activities of examined enzymes decreased in cervical cancer patients. Previous results of Kolanjiappan et al. (2002) and Manoharan et al. (2002) also demonstrated an elevated level of lipid peroxidation, lowered concentrations of GSH, vitamin E and CAT, disturbed antioxidant status as well as altered Na+K+-ATPase activity in erythrocytes of cervical cancer patients.
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儘管子宮內膜增生被認為是子宮內膜樣癌的初級階段（Hammond和Johnson，2004），但缺乏關於此類患者氧化應激與抗氧化酶之間關係的數據。迄今為止的一些研究表明，良性和惡性診斷的女性外周血和組織中脂質過氧化水平升高，AOE活性受到干擾。 Chiou和Hu（1999）報導了降低子宮頸炎和肌瘤患者的血漿和紅細胞SOD活性，而CAT和GPx的活性在宮頸炎患者中升高，在肌瘤患者中降低。 Manoharan等人對宮頸炎患者的紅細胞SOD，CAT和GPx活性進行了類似的觀察。 （2004），而宮頸癌患者檢查酶的活性下降。以前的結果Kolanjiappan等。 （2002年）和Manoharan等人。 （2002）也證實了宮頸癌患者紅細胞中脂質過氧化水平升高，GSH，維生素E和CAT濃度降低，抗氧化狀態受到干擾以及Na + K + -ATP酶活性改變。
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DISCUSSION
Evidence indicates that free radical species and their derivatives are the key denominators in a number of pathological conditions, including carcinogenesis (Maeda and Akaike, 1998). Although it is not clear whether oxidative stress and tumor result from an increased oxidant production or from a failure of antioxidant defense system (Toyokuni et al., 1995), impairment of the AOS is considered to be critically involved in such conditions. In neoplastic transformation, antioxidant enzyme activities have shown different patterns and they are highly variable in tissues and blood of patients with different types of cancer (Ahmed et al., 1999; Hristozov et al., 2001; Abiaka et al., 2002). This study indicates that antioxidant defense mechanisms are impaired in human uterine diseases and it also points to elevated levels of lipid peroxidation products, as markers of oxidative stress, in plasma of such patients. Namely, higher levels of LOOH as well as the LOOH/GPx ratio were recorded in all examined groups over those in controls, except for patients with polypus endometrii. The observed changes are in accordance with other findings where elevated lipid peroxidation was reported for patients with uterine cervicitis or myoma (Chiou and Hu, 1999) or cancer patients (Manju et al., 2002; Kolanjiappan et al., 2002). We also observed that circulating levels of lipid hydroperoxides and LOOH/GPx ratio are generally higher in subjects with either form of hyperplasia or adenocarcinoma than those found in polypus or myoma patients. Oxygen radical production, which elevates lipid peroxidation, increases with clinical progression of diseases (Bagchi and Puri, 1998; Skrzydlewska et al., 2005). Since patients with either form of hyperplasia or adenocarcinoma have 2.5-3.11-fold and 1.35-1.65-fold increase in the LOOH/GPx ratio compared to polypus or myoma subjects, respectively, this might indicate that such patients potentially have wider extent of cellular membrane alterations (van Ginkel and Sevanian, 1994) or DNA damage (Toyokuni, 1998). The increase in LOOH may also be due to the impaired antioxidant system as observed in the previous studies (Hristozov et al., 2001; Manoharan et al., 2004).
Superoxide dismutase, a scavenger of superoxide anions, along with catalase and glutathione peroxidase, the preventive antioxidants, play a very important role in protection against lipid peroxidation. In this study, SOD activities were lower in blood of all examined patient groups than in healthy subjects. Besides, decrease of SOD activity was much more pronounced in hyperplasia or adenocarcinoma patients than in subjects with polypus or myoma, thus making those individuals more vulnerable to oxidative stress. Decreased SOD activity in plasma of gynecological patients was also reported by Bhuvaraharamurthy et al. (1996), Chiou and Hu (1999), Manoharan et al. (2004). Reduction of SOD activity may be due to an increased endogenous production of ROS as evidenced by increased lipid hydroperoxides. In support of this observation, plasma LOOH were found to be negatively correlated with SOD activities in the examined patients.
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超氧化物歧化酶，一種超氧陰離子清除劑，以及過氧化氫酶和穀胱甘肽過氧化物酶，預防性抗氧化劑，在防止脂質過氧化反應中起著非常重要的作用。 在該研究中，所有檢查患者組的血液中SOD活性低於健康受試者。 此外，增生或腺癌患者的SOD活性降低比患有息肉或肌瘤的患者更明顯，從而使這些個體更容易受到氧化應激。 Bhuvaraharamurthy等報導了婦科患者血漿中SOD活性的降低。 （1996），Chiou和Hu（1999），Manoharan等。（2004年）。 SOD活性的降低可能是由於增加的脂質氫過氧化物所證明的ROS的內源性產生增加。 為了支持這一觀察結果，發現血漿LOOH與檢查患者中的SOD活性呈負相關。
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Compared with controls, significant elevation of CAT activity was recorded only in patients with hyperplasia complex while mild elevation was observed in the other groups. However, GPx activity was significantly increased only in patients with polypus endometrii. Other groups had lowered GPx activity, which was significant for the subjects diagnosed with either form of hyperplasia or adenocarcinoma. The observed changes also point to different antioxidant defense properties in various gynecological pathologies. Previous studies have reported elevated CAT and GPx activities in cervicitis patients (Chiou and Hu, 1999; Manoharan et al., 2004) and lowered activities of these enzymes in myoma patients (Chiou and Hu, 1999). In cancer patients, both lowered (Chiou and Hu 1999; Manoharan et al., 2004) and increased (Mila-Kierzenkowska et al., 2004) CAT activity in blood was observed.
Catalase is considered to play a greater role in protecting erythrocytes against oxidative stress than GPx (Gaetani et al., 1996; Mueller et al., 1997) although their significance in H202 decomposition is still not clear (Nagababu et al., 2003). Also it is well known that reactive oxygen metabolites such as hydrogen peroxide and superoxide anion increase in various pathological conditions and superoxide anion radical inactivates CAT (Kono and Fridovich, 1982) and GPx (Blum and Fridovich, 1985). Decreased SOD activity, observed in this study, would be expected to further elevate superoxide anion levels. It was also proposed that superoxide anion channel allows the transport of superoxide and other free radicals into the red cell, where they are deactivated by the erythrocyte antioxidant system (Richards et al., 1998). According to our results, in blood of examined gynecological patients, CAT activity seems to be unimpaired and GPx enzyme seems to be more sensitive to elevated levels of superoxide. In addition, lipid hydroperoxides were found to be positively correlated with CAT and negatively correlated with GPx activities in the examined patients.
Besides, decreased GPx activity, recorded in all groups except in polypus patients, might also be due to depletion of glutathione. Namely, oxidative stress was shown to induce the efflux of oxidized glutathione, consequently decreasing its content in erythrocytes and leading to their shorter life (Prchal et al., 1975; Thorn et al., 1997; Sharma et al., 2000). Similar observation was made by Manoharan et al. (2004) for cervical cancer patients and it was further supported with the finding of lowered glucose 6-phosphate dehydrogenase activity and NADPH production. Remarkably reduced glutathione reducíase activity recorded in our study is in accordance with these observations. Also, reduction of erythrocyte GPx and GR activities besides GSH depletion is considered responsible for increased heme degradation as shown by Nagababu et al. (2003). Similar findings on GPx and GR activities in our study could also point to further deterioration of oxidative stress conditions based on heme degradation in gynecological patients.
In summary, this study shows that patients with polypus or myoma, or either form of hyperplasia or adenocarcinoma have enhanced lipid peroxidation and LOOH/GPx ratio, as well as altered activities of antioxidant enzymes in peripheral blood circulation. Although alterations vary with the enzyme type and diagnosis, both reduction in antioxidants and elevation of lipid peroxidation were observed in general. The lowered activity of antioxidant enzymes in gynecological patients could be a result of disturbed redox status, while elevated lipid peroxidation seems to be a consequence of the disease rather than its cause. Furthermore, the LOOH/GPx ratio, which increases with the severity of the disease, suggests a greater oxidative stress status that can be related to the different uterine pathology. Such ratio could also be taken as an indicative parameter of oxidative stress in blood of gynecological patients.
It is known that in response to acute oxidative stress antioxidants may be consumed to prevent oxidative damage, and then may be supplied through the antioxidant network. However, in the cases of the observed gynecological pathologies it seems that prolonged oxidative stress elevates free radical production and induces consumption of antioxidants, which in turn further aggravate the free radical damage and increase the chance of developing uterine cancer. Indeed, the results obtained in this study show that observed changes of AO status, LOOH level, and LOOH/GPx ratio in peripheral circulation of gynecological patients are more pronounced in premalignant (hyperplastic) and malignant (ACE) lesions, compared with benign uterine changes (polypus and myoma). Further investigation should determine whether lipid hydroperoxides level and AOE activities in blood of such patients might be used as additional parameter in clinical evaluation of gynecological disorders.
The work was financially supported by the Ministry of Science and Environmental Protection of the Republic of Serbia (塞爾維亞) (Grant 143035).
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Corresponding author: Dr. Snezana B. Pajovic, Principal scientist, Laboratory for Molecular Biology and Endocrinology, Vinca Institute for Nuclear Sciences, P. O. Box 522, 11001 Belgrade, Serbia (塞爾維亞), Tel +381 (11) 2455 561, Fax +381 (11) 2455 561, E-mail: pajovic@vin.bg.ac.yu
Received: April 13, 2006. Accepted: August 29, 2006
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