Structure Of Streptozotocin

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Averrhoa bilimbi Linn belongs to the family Oxalidaceae (Fig. 1). It is a small tree growing to 15 m tall with a trunk diameter up to 30 cm. Young parts of the tree are covered with long-persistent, yellowish to rusty, velvety hairs. Leaves are often crowded at the ends of the branches with 7-19 leaflets, each measuring up to 12 cm by 4 cm, variable in shape; lateral veins have 6-14 pairs. Flowers are borne in dense, fascicled, pendulous clusters on bare branches and on knobby protuberances along the tree trunk; the calyx is yellowish-green, petals are red to purple. Fruits are rounded to blunt, angular in cross-section, up to 10 cm by 5 cm, and fleshy and juicy but acidic when ripe. Though it is widely cultivated in the lowlands of Southeast Asia, the tree's country of origin is unknown but tropical America has been suggested. Flowering and fruiting occur intermittently throughout the year. Other names of the tree are Averrhoa obtusangula Stokes; Belimbing asam, Belimbing buluh, Belimbing wuluh (Malay, Javanese); Kamias, kalamias, Iba, Kolonanas (Tag); and Ta-ling-pring (Thai) (1).

Kalamias Tree
Figure 1 Averrhoa bilimbi leaves and fruits.

A. Chemical Constituents

The chemical constituents of A. bilimbi that have been identified include amino acids, citric acid, cyanidin-3-O-h-d-glucoside, phenolics, potassium ion, sugars, and vitamin A in fruits (2).

B. Ethnopharmacological Uses

A. bilimbi has been used as an antibacterial, antiscorbutic, astringent; postpartum protective medicine; in treatment of fever, inflammation of the rectum, and diabetes (prepared from leaves); in treatment of itches, boils, rheumatism, cough, and syphilis (paste of leaves); in treatment of scurvy, bilious colic, whooping cough, hypertension, and as a cooling drink (juice of preserved fruits); in treatment of children's cough (syrup of flowers); for stomachache (fruits), mumps, and pimples (prepared from leaves) (1).


The single-high-dose-STZ-induced diabetic rat is one of the animal models of human insulin-dependent diabetes mellitus (IDDM), or type I diabetes mellitus. In this model, diabetes arises from irreversible destruction of the h-islet cells of the pancreas by streptozotocin, causing degranulation or reduction of insulin secretion. In this type I model of diabetes, the insulin is markedly depleted, but not absent (3).

The chemical structure of STZ consists of a glucose moiety (Fig. 2) with a highly reactive nitrosourea side chain that is thought to initiate its cytotoxic action. As shown in Figure 3, the glucose moiety directs this agent to the pancreatic h cells, where it binds to a membrane receptor to cause structural damage (4). The deleterious effect of STZ results from the generation of highly reactive carbonium ions (CH3) that cause DNA breaks by alkylating DNA bases at various positions, resulting in activation of the nuclear enzyme poly (ADP-ribose) synthetase, thereby depleting the cellular enzyme substrate (NAD + ), leading to the cessation of NAD + -dependent energy and protein metabolism. This in turn leads to reduced insulin secretion (5). It has been suggested that free-radical stress occurred during h-cell destruction mediated by mononuclear phagocytes and cytokines (6,7). Since free-radical scavenger was demonstrated to protect against the diabetogenic properties of STZ, it is likely the oxidative stress may play a role in determining STZ toxicity (8). However, some poly (ADP-ribose) synthetase inhibitors, such as nicotinamide and 3-aminobenzamide, could prevent the onset of diabetes (9).

A. Hypoglycemic Activity of A. bilimbi in STZ-Diabetic Wistar Rats

STZ-induced diabetic male Wistar rats were given five intraperitoneal (i.p.) injections of the 80% ethanolic leaf extract of A. bilimbi (ABe) at 300 mg/kg or the water extract of the fruits of A. bilimbi (ABw) at 100 mg/kg or its corresponding vehicle, daily for 7 days. Fasting blood glucose estimations and

Figure 2 The chemical structure of streptozotocin.

Figure 2 The chemical structure of streptozotocin.

Averrhoa Bilimbi Leaf Cholesterol

impaired insulin

Figure 3 The mechanism of pancreatic h-cell destruction by streptozotocin.

impaired insulin

Figure 3 The mechanism of pancreatic h-cell destruction by streptozotocin.

food intake measurement were done on all the days of injection. The results of this preliminary study showed decreases in fasting blood glucose levels and mean daily food intake in the ABe- and ABw-treated STZ-diabetic rats (2).

B. Hypoglycemic Activity of A. bilimbi in STZ-diabetic Sprague-Dawley (SD) Rats

1. Effect on Oral Glucose Tolerance in Normal and Diabetic SD Rats

In the oral glucose tolerance test (OGTT) in both normal and STZ-diabetic SD rats, distilled water (control), a reference drug, metformin (500 mg/kg), or each of three different doses of ABe (125, 250, and 500 mg/kg) was orally administred to groups of four to five rats each after 16-hr fast. Thirty minutes later, glucose (3 g/kg) was orally administered to each rat with a feeding syringe (10). The blood glucose levels of the normal and diabetic rats reached a peak at 60 min after the oral administration of glucose and gradually decreased to preglucose load level. Of the three different doses, 125, 250, and 500 mg/kg, the lowest dose, i.e., 125 mg/kg, caused attenuation in the blood glucose level in both normal and diabetic rats (11). Similarly, its semipurified fractions, such as the aqueous fraction (AF) as well as the butanol fraction (BuF) at 125 mg/kg, caused attenuation in blood glucose level in STZ-diabetic rats (12). Moreover, the daily oral administration of ABe, AF, and BuF at a dose of 125 mg/kg twice a day for 14 days to STZ-diabetic SD rats caused a decrease in the blood glucose level (11,12).

2. Blood-Lipid and Cholesterol-Lowering Effect

The daily administration of ABe per orally (125 mg/kg twice a day) for 14 days to STZ-diabetic SD rats caused a reduction in the serum triglycerides and an increase in HDL cholesterol. However, ABe did not decrease the serum cholesterol and LDL cholesterol. This leads to an increase in the antiathero-genic index and HDL cholesterol:total cholesterol ratio (11). Moreover, the daily administration of ABe (125 mg/kg) and metformin (500 mg/kg) to STZ-diabetic rats twice a day for 2 weeks caused a reduction in food and water intake and an increase in body weight (11). Since ABe increased HDL cholesterol, it significantly increased the antiatherogenic index and HDL cholesterol:total cholesterol ratio. ABe thus has the potential to prevent the formation of atherosclerosis and coronary heart disease, which are the secondary diabetic complications of severe diabetes mellitus (13). In contrast, metformin failed to increase the HDL-cholesterol level and did not increase the antiatherogenic index and HDL cholesterol:total cholesterol ratio. However, it has been reported that metformin can reduce the blood lipid parameters in nondiabetic patients with coronary heart disease (14). Hence, ABe contains a hypolipidemic principle(s) that probably acts differently from metformin (11).

3. Effect of A. bilimbi on Liver and Kidney Thio-Barbituric-Acid-Reactive Substances (TBARS) in STZ-Diabetic SD Rats

ABe and AF treatment at a dose of 125 mg/kg in STZ-diabetic SD rats reduced the TBARS levels in the kidneys, but not in the liver. The lack of change in TBARS levels in the liver of ABe-, AF-, and BuF-treated diabetic rats could again reflect the resistance of the liver to the oxidative stress in the diabetic state. It is significant to note that neither AF nor BuF affects this capacity adversely. Since ABe and AF have the ability to reduce the formation of TBARS, they could potentially prevent platelet aggregation and thrombosis (11,12).

4. Effect of A. bilimbi on Insulin in STZ-Diabetic Rats

Similar to other hypoglycemic agents such as tungstate and vanadate (15-17), AF caused a time-dependent hypoglycemic effect after twice-a-day oral administration of 125 mg/kg for 7 and 14 days in STZ-diabetic SD rats. On the other hand, when the STZ-diabetic rats were treated with 125 mg of BuF/ kg, the serum insulin level was higher on both day 7 and day 14. The elevation in serum insulin in the AF- and BuF-treated STZ-diabetic rats could be due to either the insulinotropic substances present in the fractions, which induce the residual functional h cells to produce insulin, or the protection of the functional h cells from further deterioration so that they remain active and produce insulin. However, except for the level in the AF-treated group on day 14, the insulin levels were well below the normal insulin level in control rats, suggesting that they may not be sufficient to lower the blood glucose to its normal level in STZ-diabetic rats (12). This indicates a possible insulin-releasing action of ABe in STZ-diabetic rats like the extracts of Medicago sativa (18), Eucalyptus globulus (19), and Sambucus nigra (20) which have been shown to possess insulin-releasing action both in vitro and in vivo.

5. Effect of A. bilimbi on Liver Glucose-6-Phosphatase Activity and Glycogen in STZ-Diabetic Rats

Glucose-6-phosphatase catalyzes the final step in glucose production by the liver and kidney. STZ has been reported to increase the expression ofglucose-6-phosphatase mRNA, which contributes to the increased glucose-6-phos-phatase activity in diabetes mellitus (21). Overproduction of glucose by the liver is the major cause of fasting hyperglycemia in both insulin-dependent and non-insulin-dependent diabetes mellitus. Ninety percent of partially pancreatectomized diabetic rats have a > 5-fold increase in the messenger RNA and a 3-4 fold increase in the protein level of the catalytic subunit of hepatic glucose-6-phosphatase. Prolonged hyperglycemia may thus result in overproduction of glucose via increased expression of this protein (22). Normalization of the plasma glucose concentration in diabetic rats with either insulin or the glycosuric agent phlorizin normalized the hepatic glucose-6-phosphatase messenger RNA and protein within approximately 8 hr. However, phlorizin failed to decrease hepatic glucose-6-phosphatase gene expression in diabetic rats when the fall in the plasma glucose concentration was prevented by glucose infusion (22). This indicates that in vivo gene expression of glucose-6-phosphatase in the diabetic liver is regulated by glucose independently of insulin. The AF fraction, like the biguanide drug metformin, appears to control the increase in blood glucose in STZ-diabetic rats by decreasing the activity of glucose-6-phosphatase in the liver. This could be one of the mechanisms for the suppression of blood glucose concentration in the diabetic rats (12). Similarly, extracts of plants such as Zizyphus spina-christi reduced serum glucose level, liver phosphorylase, and glucose-6-phosphatase activities, and increased serum pyruvate level after 4 weeks of treatment. Likewise 60% ethanolic extract of Coccinia indica and 95% ethanolic extract of Momordica charantia extracts were found to lower blood glucose by depressing its synthesis, on the one hand, by depressing key gluconeogenic enzymes glucose-6-phosphatase and fructose-1,6-bisphospha-tase and, on the other, by enhancing glucose oxidation by the shunt pathway through activation of its principal enzyme, glucose -6-phosphate dehydro-genase (23). However, AF and BuF treatment in STZ-diabetic rats did not affect hepatic glycogen content (12). Similarly, vanadate compounds have been shown to inhibit hepatic glucose-6-phosphatase activity thereby reducing blood glucose levels in nonobese diabetic (NOD) mice (24).

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