INTRODUCTION:

Air pollution has always been a trans-boundary environmental issue and a matter of global concern for past decades. High concentrations of air pollutants due to numerous anthropogenic activities influence the air quality. Sulfur dioxide is commonly generated from combustion of fuel containing sulphur like coal and oil, metal smelting and other industrial process. Sulphur dioxide is a highly water soluble irritant gas which gets rapidly penetrate the nasal passages during pulmonary respiration¹. Albeit, the respiratory system is the prime target of sulphur dioxide toxicity but it can also affect other organs and systems by means of entering into the systemic circulation through the blood stream².

The exposure of sulphur dioxide induces the histopatholgical changes in liver and also causes the alterations in the serum enzymes level, besides, alter the lipid biochemistry^3-7. SO₂ is highly toxic to blood and decreases the Hb. Level⁸. The combination of SO₂ and NO₂ is toxic to the brain lipid content³.

The SO₂ has also been altered the serum immunoglobulin level in rat which is an indication of immunosuppressive effect of SO₂⁹. It is an oxidant, causes adverse health effects by means of inducing the generation of free radicals¹⁰. Proteins are the nitrogen containing substances of immense importance to the living beings for the formation of body tissues, enzymes, hormones, immunoglobulins and other intracellular and extracellular proteins¹¹. Bile is secreted by the hepatic cells and plays an important role in emulsification of fat.

Aloe vera is a semi-tropical, stemless succulent plant. It is commonly known as “Gheekanwar”, is a cactus like plant with green, dagger-shaped leaves that are fleshy, tapering, spiny marginated and filled with clean viscous gel^12-13. A. vera contains a multitude of essential vitamins, minerals, a wealth of amino acids, saccarides, anthraquinones and enzymes. It has antioxidative, anti-inflammatory, anti-bacterial, anti-viral-wound healing, anti-fungal, anti-diabetic and stimulation of hematopoiesis¹⁴. The aloesin derivatives of A. vera possess strong OPPH radical and superoxide anion scavenging activities^15-16. The Aloe vera plant juices are having efficiency in the gastroprotective activity and has also been found to be immunomodulatory, hypolipidemic, hypoglycemic and heamatinic properties.

The present study has been done to evaluate the hepatoprotective effect of Aloe vera on sulphur dioxide induced alterations in albino rats.

MATERIALS AND METHODS:

Animals:

Adult healthy male wistar albino rats of equal weight ranging from 150-195g were kept in polypropylene cages. Inbred colony of albino rats were maintained at animal house of zoology department in standard condition of temperature 25+2°C and relative humidity 50+0.5% and desired light dark cycle (12-12 hrs.). The rats were fed on standard laboratory animal diet commercial food pellets, golden feed, New Delhi and water ad libitum. Experimental animals acclimated for one month prior to experiment. The experimental protocol used in this study was approved (Reg.-1608/CPCSEA) by the Institution Animal Ethical Committee (IAEC) for the purpose of control and supervision on experimental animals of Dr. B. R. Ambedkar University, Agra.

Generation of SO₂:

80ppm SO₂ gas was generated by controlled action of 5% sulphuric acid on sodium sulphite in a sulphur dioxide generator ¹⁷. Rats were exposed in fumigation chamber (AP 07 model SFC 120), Standard Appliances, Varanasi.

Preparation of Aloe vera aqueous extract of leaf pulp:

Fresh leaves of Aloe vera were collected from the Dewan farms, Barara, Agra. The thick epidermis was selectively removed and inner colorless mucilaginous pulp was taken. The fresh pulp (1kg) of Aloe vera grinded in spice grinder and extracted with one litre of distilled water and kept with magnetic stirrer in cold room temperature for 48 hours. The suspension was filtered by whatman No. 1 filter paper and residue was used for experimentation¹³.

The dose of Aloe vera extract (200mg/kg b.wt./day) was administered in rats by oral gavage. The dose was selected by as guideline as per traditional medicinal system¹⁸.

Experimental design:

The rats were randomly divided in to control set (1) and experimental sets (2 & 3) of ten rats each.

Control set (1): without SO₂ Exposure

Experimental set (2): Exposed to SO₂ gas (80 ppm/hr/day) for 30 and 60 days

Experimental set (3): Exposed to SO₂ gas (80 ppm/hr./day) along with oral administration of freshly prepared aqueous extract of Aloe vera (200 mg/kg b.wt./day) for 30 and 60 days.

Collection of blood samples:

After stipulated exposure period rats of control and experimental groups were sacrificed and blood samples were collected from the ventricles of heart for the estimation of serum lipid profile.

Biochemical study:

The serum total bilirubin, conjugated and unconjugated bilirubin were estimated by the Autozyme colorimetric kit method¹⁹. The serum total protein was estimated by modified Biuret and Dumas Method²⁰. Serum enzymatic activities (ALP, ALT AST and GGT) were measured by the International Federation of Clinical Chemistry (IFCC) kit methods^21-22.

Statistical analysis:

The results were expressed as Mean±S.Em. were signified by using Student’s ‘t’ test. Statistical calculation was carried out by using one way ANOVA with the help of computer statistical program KpKy plot (version-3.0).

RESULTS:

Results of present study showed a significant increase (P<0.05) in SALP, SAST, SALT and SGGT activities in 80ppm SO₂ gas exposed rats comparison to control group after 30 days, while a highly significant increase (P<0.01) in serum liver enzymes level at 80ppm SO₂ gas exposed rats after 30 and 60 days respectively (table-1).

The SO₂ exposure resulted in highly significant decrease (p<0.01) in serum total protein after 30 days while, very highly significant decrease (p<0.001) after 60 days respectively. The non-significant decrease (p>0.05) in serum albumin and serum globulin and significant decrease (p<0.05) in serum albumin and serum globulin have also been reported after 30 and 60 days respectively (table-2).

The results of the present study showed that the exposure to SO₂ gas resulted in non-significant increase in serum bilirubin, serum conjugated bilirubin and serum unconjugated bilirubin (p>0.05) after 30 days while, significant increase (p<0.05) after 60 days respectively (table-3).

The oral supplementation of Aloe vera significantly normalized the toxicological alterations induced by the SO₂ exposure in albino rat.

Table-1 Effects of Aloe vera on serum enzymes (U/l) in 30 and 60 days Sulphur dioxide exposed albino rat.

Sets

Exposure and pre-exposure supplementation

30 days

60 days

Range (Mean±S.Em)

SALP

SGOT

SGPT

SGGT

SALP

SGOT

SGPT

SGGT

Control set-1

Ambient air

155-168

(160.6±2.18)

105-121

(112.6±2.66)

42-56

(48.20±3.02)

12.80-17.42

(15.18±0.87)

156-169

(161.2±2.50)

108-125

(113.8±3.12)

40-56

(49.00±3.21)

13.23-17.52

(14.85±0.80)

Experimental set-2

80ppm SO₂ gas

165-200

(181.6±6.86) ↑*

115-130

(123.2±2.89) ↑*

52-65

(58.60±2.34) ↑*

15.60-23.89

(19.86±1.38) ↑**

175-218

(196.4±7.05) ↑**

119-138

(130.6±3.67) ↑**

59-67

(62.60±1.50) ↑***

15.20-25.63

(21.90±1.86) ↑**

Experimental set-3

80ppm SO₂ gas

Aloe vera

156-167

(159.6±2.56) ↓*

109-119

(113.2±1.85) ↓*

43-55

(47.20±2.63) ↓*

12.95-17.85

(15.32±0.87) ↓*

150-169

(159.8±3.56) ↓***

109-118

(112.6±1.69) ↓**

41-52

(47.00±1.87) ↓***

14.95-17.41

(16.07±0.41) ↓*

N.S.=Non-Significant↓=Decrease*=Significant ↑=Increase S. Em= Standard Error of mean**=Highly significant***=Very highly significant

Table-2 Effects of Aloe vera on serum total protein, serum albumin and serum globulin (g/dl) in 30 and 60 days Sulphur dioxide exposed albino rat

Sets

Exposure and pre-exposure supplementation

30 days

60 days

Range (Mean±S.Em)

Total protein

Albumin

Globulin

Total protein

Albumin

Globulin

Control set-1

Ambient air

5.90-6.12

(6.04±0.04)

2.6-4.0

(3.40±0.26)

1.8-2.7

(2.20±0.17)

5.23-6.25

(5.83±0.11)

2.7-4.8

(3.44±0.37)

1.9-2.6

(2.18±0.12)

Experimental set-2

80ppm SO₂ gas

4.58-5.95

(5.13±0.22) ↓**

2.4-3.2

(2.80±0.16) ↓*

1.2-2.2

(1.70±0.17) ↓*

3.25-4.30

(3.86±0.18) ↓***

1.8-3.2

(2.30±0.25) ↓**

1.1-2.0

(1.52±0.17) ↓*

Experimental set-3

80ppm SO₂ gas

Aloe vera

5.56-6.50

(6.03±0.15) ↑*

2.3-3.8

(3.24±0.27) ↑^N.S

1.4-2.4

(2.06±0.18) ↑^N.S

5.34-6.35

(5.86±0.18) ↑***

2.4-3.9

(3.36±0.27) ↑*

1.7-2.4

(2.02±0.12) ↑*

N.S.=Non- Significant↓=Decrease**=Highly significant*=Significant ↑= Increase***=Very highly significant S.Em= Standard Error of mean

Table-3 Effects of Aloe vera on serum total bilirubin, conjugated and unconjugated bilirubin level (mg/dl) in 30 and 60 days Sulphur dioxide exposed albino rat

Sets

Exposure and pre-exposure supplementation

30 days

60 days

Range (Mean±S.Em)

Total bilirubin

Conjugated bilirubin

Unconjugated bilirubin

Total bilirubin

Conjugated bilirubin

Unconjugated bilirubin

Control set-1

Ambient air

0.55-0.98

(0.67±0.08)

0.2-0.3

(0.22±0.02)

0.30-0.78

(0.48±0.08)

0.52-1.10

(0.69±0.10)

0.1-0.3

(0.22±0.04)

0.22-0.90

(0.47±0.12)

Experimental set-2

80ppm SO₂ gas

0.55-1.86

(1.12±0.27) ↑^N.S

0.2-0.4

(0.30±0.03) ↑^N.S

0.32-1.46

(0.82±0.25) ↑^N.S

0.62-2.35

(1.49±0.31) ↑*

0.3-0.5

(0.36±0.04) ↑*

0.32-2.05

(0.93±0.34) ↑^N.S

Experimental set-3

80ppm SO₂ gas

Aloe vera

0.55-1.25

(0.77±0.12) ↓^N.S

0.2-0.3

(0.26±0.02) ↓^N.S

0.30-1.00

(0.50±0.13) ↓^N.S

0.59-1.22

(0.84±0.15) ↓^N.S

0.1-0.4

(0.24±0.05) ↓^N.S

0.19-1.02

(0.60±0.15) ↓^N.S

N.S.=Non-Significant↓=Decrease*=Significant↑=Increase S. Em= Standard Error of mean

DISCUSSION:

In the present study, a significant increase in serum total bilirubin, conjugated and unconjugated bilirubin with increase in time period of SO₂exposure is correlated with the hepatic injury in albino rats. The unconjugated bilirubin is carried by albumin to the liver, where it is converted into conjugated and gets water soluble. Because of decrease in concentration of albumin due to hepatic injury, unconjugated bilirubin is not converted in conjugated bilirubin as a result of which increase in level of serum unconjugated bilirubin has been observed²³. The bilirubin level rises has been reported in the diseases of hepatocytes, obstruction to biliary excretion into duodenum and in hemolysis²⁴. Similarly, increased level of total and conjugated bilirubin due to hepatocellular damage and biliary tract disease have also been observed ²⁵. In support of present findings, the elevation in level of total bilirubin and direct bilirubin in various forms of liver disease and intravascular hemolysis in fire fighters exposed to fire smoke²⁶.

In the present study, a significant decrease in serum total protein, serum albumin and serum globulin is due to the inflammatory response induced by sulphur dioxide gas. The increase in membrane permeability leads to the leakage of protein from serum to the site of oxidative injury due to the inflammatory mechanism caused by oxidation of cell membrane proteins and its fraction. In support of present findings, decreased level of serum total protein and albumin, histopathological changes in the liver of rats have been observed after inhalation of SO₂ gas which shows degeneration of hepatocytes and necrosis. The decreased level of serum total protein and hypoalbuminaemia occur in liver diseases having significant destruction of hepatocytes²⁴.

In the present study, the activity of serum enzymes viz. serum alkaline phosphatase (SALP), serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT) and serum gamma glutamyl transferase (SGGT) increases significantly after sulphur dioxide inhalation is due to production of free radicals and tissue injury by the inflammatory action of toxic gas. In inflammatory states, the lost of soluble enzymes through an impaired membrane might act as a stimulus to increased synthesis when an organ or a cell is damaged due to any toxicity, a greater amount of intracellular enzymes, leaves the cell and enters the serum. The damage of certain tissue and release of enzymes into blood causes elevation of enzyme level in blood. The extent of elevation in serum activity of these enzymes is proportional to severity of damage and concentration of enzymes in plasma¹¹. Similar to the present findings, free radicals are generated by sulphur dioxide, which leads to lipid peroxidation, altering membrane properties ultimately affecting protective enzyme systems in rat ²⁷. The increase in serum enzyme activity due to oxidative damage caused by SO₂gas exposure in mice²⁸. Similar to the present findings, occupational sulphur dioxide inhalation results in higher lipid peroxidation and membrane fragility²⁹.

Present findings supported by the report about the generation of free radicals on exposure to air pollution³⁰. The accumulation of free radicals in hepatic cellular components may increase cellular degeneration of liver causing elevation in serum enzyme activity in humans³¹. The sulphur dioxide inhalation results in structural and functional membrane damage due to generation of free radicals, which results in premature cell death³².

Alkaline phosphatase is a microsomal enzyme, which arise mainly from the hepatocyte lining of bile canaliculi, sinusoidal surface of liver cells, osteoblast cells of bone and placenta. In the present study, a very highly significant increase in the activity of serum alkaline phosphatase is attributed to the damaging effect of sulphur dioxide on liver, which results in leaching of isoenzymes of hepatic origin; much of which escapes into circulation causing increase serum alkaline phosphatase activity. Similar to the present findings, at time of biliary obstruction new alkaline phosphatase are synthesized in hepatocytes causing increase in enzyme activity in rats³³.

In support of present findings, hepatocellular damage is the most common cause of release of membrane bound serum alkaline phosphatase³⁴. The sulphur dioxide can also cause reduction of enzyme activities of superoxide dismutase³⁵.

The serum glutamic oxaloacetic transaminase (SGOT) and the serum glutamic pyruvic transaminase (SGPT), belong to the category of non-plasma specific enzymes. Both transaminases are highly concentrated in the liver. Serum glutamic oxaloacetic transaminase is a mitochondrial enzyme, while serum glutamic pyruvic transaminase is a cytosolic enzyme. Serum glutamic pyruvic transaminases are of diagnostic significance, widely distributed intracellular enzyme and it escapes into the circulating blood in which its activity is normally low, is a sensitive index of tissue damage³⁶.

In the present study, very highly significant increase in transaminases activity is attributed to liver injury in albino rats due to toxic action of sulphur dioxide gas. This causes leakage of enzymes from damaged cells; due to increased permeability of the hepatocellular membrane ultimately leads to necrosis. Similar findings have been reported notably raised transaminases in liver injury due to inhalation of toxic gas³⁷. Similarly, injury to the liver, whether acute or chronic, eventually results in an increased serum concentration of transaminases has also been observed³⁸. The similar views regarding increase in serum transaminases and alkaline phosphatase after inhalation of toxic fumes in rats³⁹. In support of present findings, the elevation in ALT and AST level is due to hepatic cell damage in fire fighters exposed to fire smoke has been reported²⁶.

Gamma glutamyl transferase is a biliary enzyme, which markedly increase in hepatic necrosis and causes intra-hepatic and extra-hepatic obstructions of bile ducts¹¹. In the present study, a significant elevation in the activity of serum gamma glutamyl transferase is correlated with the hepatic injury in albino rats due to toxic action of sulphur dioxide gas. In support of present findings, the elevation in GGT level is due to hepatic cell damage in fire fighters exposed to fire smoke has previously been reported²⁶.

The leaves of Aloe vera contain 99 phytonutrients which have therapeutic properties such as immunostimulation, anti-inflammatory and anti-oxidants etc. Anti-inflammatory activity of mannose-6-phosphate is believed to resemble the effects observed for acetylated mannan in aloe gel, which reduces inflammation induced by promotion of prostaglandin synthesis as well as increased infiltration of leucocytes. Aloe vera have glutathione peroxidise activity, superoxide dismutase enzymes and a phenolic antioxidant were found to be present, which may be responsible for the antioxidant effects¹⁴. Aloe also contains three anti-inflammatory fatty acids: cholesterol, compesterol and β-sitosterol (plant sterols). These agents are the source of Aloe’s effectiveness in treating all kinds of internal and external inflammations of the liver. Additionally, β-sitosterol is a powerful agent in helping to lower bad cholesterol levels. Further, Aloe vera gel contains three malic acid acylated carbohydrates: veracylglucans A, B and C. All three compounds demonstrate anti-inflammatory effects ^40-41.

The detoxification properties of Aloe vera juice act to detoxify the blood stream, improve circulation and detoxify body by clean the colon. Carrisyn, an extract of Aloe vera has been shown to stimulate the production of infection-fighting blood cells and in so doing strengthen the immune system⁴². The aloesin derivatives of Aloe vera possess strong DPPH radical and superoxide anion scavenging activities ^15-16. Anti-inflammatory properties of Aloe vera have also been reported in rats⁴³.

A significant reduction in elevated level of serum total bilirubin and serum enzymes activity is correlated with the hepatocurative efficacy of Aloe vera against oxidative damage induced by SO₂ in rats. Aloe vera act as antioxidant by scavenging prooxidant free radicals and stimulate the regeneration of liver cells. It also exhibits a regulatory action of cellular membrane permeability and increase in its stability against hepatic injury. Reduction in total bilirubin and enzymes activity is also supported by the improvement in histopathology of liver tissue in rats. Aqueous extract of Aloe vera significantly capable of restoring integrity of hepatocytes indicated by improvement in liver function. Similarly, the aqueous extract was found to improve liver function by normalizing the activity of liver specific enzyme ALT in rats⁴⁴. Similar to the present findings, after supplementation of Aloe vera extract decreased in serum ALP and ALT activities in diabetic rats⁴⁵. Similarly, after supplementation of Aloe vera, the activity of AST and ALT decreases in serum against arsenic induced toxic effects on rats⁴⁶. Present findings are agreement with the findings that the rise in serum levels of GOT, GPT, GGT and ALP is attributed to the damaged structural integrity of the liver induced lindane and after administration of Aloe vera inhibits the acute liver toxicity and reduction of serum activity in rats⁴⁷.

Similar to the present findings, the extract of Aloe vera showed restoration of serum transaminases, alkaline phosphatase and serum bilirubin as evident by hepatoprotective activity in mice⁴⁸. Similarly, the treatment with Aloe vera exhibited a significant reduction in SGOT, SGPT, SALP and serum bilirubin level, indicating a good degree of protection against the toxic substances in rats⁴⁹.

Supporting findings have been reported that the normalcy of SGOT, SGPT and ALP towards the respective normal values by herbal formula is an indication of the stabilization of plasma membranes as well as repair hepatic tissue damage caused by carbon tetrachloride⁵⁰. This effect is in agreement with the commonly accepted view that serum levels of transaminases and ALP return to normal with healing of hepatic parenchyma and the regeneration of hepatocytes in wistar albino rats. The elevated levels are primarily due to the leakage of cellular enzymes into the blood stream leading to their increase in serum, after treatment with partysmart rats could be a manifestation of reduction in cell membrane disturbances and oxidative stress by free radical scavenging and antioxidant activity in wistar rats^51-52.

In the present study, a significant increase in serum total proteins is correlated with reduction in liver tissue damage resulting stimulation of protein synthesis and regeneration of liver cells due to antioxidative activity of Aloe vera against SO₂ toxicity in rats. Aloe vera increases the total protein level due to positive nitrogen balance. Similar to the present findings, a significant elevation in serum total protein, albumin and globulin level of alcoholic rats after administration of partysmart⁵².

The findings of the present study is also affirmed that Aloe vera gel extract restored the serum enzyme level and total protein level in streptozotocine induced diabetes mellitus in mice. Similarly, Aloe vera have anti-inflammatory, antioxidant, and curing wound herbal substance, could prevent these adverse events and might be used as an adjunctive therapy for APAP-induced hepatitis and significantly restored the increased SGOT and SGPT level in paracetamol induced hepatitis in mice⁵³. The administration of Aloe vera significantly overcomes the increased level of serum total protein and ALP level in ethanol treated rats. The serum biochemistry is one of the basic indicator and fundamental marker in various pathologies and pathogenic agents. The oral administration of Aloe vera improves the serum total proteins, serum albumin and globulin level which indicate that it is a hemato-modulator. The liver is the most vital organ for the metabolism of drugs and other toxicants. Liver damage results in altered bilirubin and serum enzyme level, elevation in serum bilirubin indicates liver damage as confirmed by the changes in the activities of liver enzymes (SGOT and SGPT).Thus, the increased level of bilirubin observed in mice in could be attributed to liver damage. However, the decrease in bilirubin levels in treated mice is indicative of reversal of liver damage by Aloe vera ⁵⁴.

CONCLUSION:

In the light of present study we can conclude that, the toxicity of sulphur dioxide gas increases with increase in time period of exposure in albino rats, while after oral administration of Aloe vera, the toxic effects of sulphur dioxide gas have mitigated to a greater extent and altered values reach upto control values in albino rats.

ACKNOWLEDGMENT:

The authors would like to thank U.G.C, New Delhi for providing financial support to complete this valuable research work.

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Received on 22.12.2017 Modified on 21.03.2018

Res. J. Pharmacology & Pharmacodynamics.2018; 10(4): 149-155.

DOI: 10.5958/2321-5836.2018.00027.7

Detrimental effects of Sulphur Dioxide Gas on Liver Parameters and its Modulation by Aloe Vera