Comparison of chemicals
AQs, including rhein, emodin, chrysophanol, aloe emodin, emodin methyl ether, aurantio-obtusin, obtusin, obtusifolin, and physcion, among others[10,11], are components of many herbal medicines. These medicines include Cassiae semen (Juemingzi in Chinese medicine); Rhizoma et Radix Polygoni Cuspidatum (Huzhang in Chinese medicine); Radix et Rhizoma Rhei (Dahuang in Chinese medicine)[13,14]; Radix Polygoni Multiflori (Heshouwu in Chinese medicine); Aloe (Luhui in Chinese medicine); and Senna leaf (Fanxieye in Chinese medicine). For thousands of years, they have all been used as traditional medicines to treat constipation in many East Asian countries, including China, Japan, and Korea.
In plants, AQs are predominantly glycosylated, and after oral administration, cannot be broken down by α-glucosidase in gastric acid or in the small intestine, because of the β-glycosidic bond between the sugar and the AQ ring. Thus, AQs go directly into the large intestine, where they are broken down by bacterial beta-glucosidases and reductases. AQ derivatives stimulate intestinal nerves, inhibit Na+-K+-ATP enzymes, increase retention of bowel fluid, induce peristalsis in the large intestine, reduce absorption of colonic fluid and Na+, and promote defecation.
AQ-related drugs, which are often used to establish cathartic colon models, include rhubarb, total AQ in rhubarb, rhein, and emodin, among others. Radix et Rhizoma Rhei (rhubarb) is the most common drug used to establish cathartic colon animal models because of its low cost and availability. Total AQ in rhubarb is an AQ extract from rhubarb. Rhein is a lipophilic AQ, which has no cathartic effect. However, its metabolite, anthrone rhein, which is formed by the action of intestinal microorganisms, has cathartic activity. Emodin is an AQ derivative that has been isolated mainly from the rhizome of rhubarb in Polygonaceae. Many experiments have proved that emodin can significantly increase movement of intestinal smooth muscle and promote secretions from the intestinal epithelium. Therefore, emodin has been used as a laxative for many years.
Although rhubarb has been widely used to induce cathartic colon animal models in many studies, its composition is complex, its laxative effects are unstable, and it can be easily affected by its source, variety, processing, and storage methods. In addition, the long-term use of rhubarb may affect other physiological systems, and thereby affect the development of cathartic colon. Pharmacological studies have shown that rhubarb has both laxative and antidiarrheal components. When rhubarb was soaked or decocted for a short time, the dissolution rates of AQ glycosides and other diarrheal components can be high. Nevertheless, the dissolution rate of tannin and other antidiarrheal components may be high. Therefore, when rhubarb is used to induce cathartic colon animal models, the effects of decoction time on the bioactivity of rhubarb should be considered.
Rhein is a monomer with stable pharmacodynamics. Its quality remains stable and its concentration is easy to control.
The establishment of cathartic colon animal models by emodin and total AQ in rhubarb is rare, and needs further verification. Interestingly, the intestinal wall reportedly becomes thinner, telescopic function is poorer, and the time required for free stretching is prolonged in the cathartic colon model induced by total AQ in rhubarb. This is consistent with the findings of Smith in patients with cathartic colon.
In addition, diphenylmethane drugs and their derivatives, including phenolphthalein, bisacodyl, and sodium picosulfate, among others, are also commonly used to establish models of cathartic colon. Among these agents, phenolphthalein is the most common, even though it is almost insoluble in water. After oral administration, the soluble sodium salt is produced in the alkaline environment of the intestinal tract, which stimulates the intestinal plexus and directly affects the intestinal smooth muscle to increase intestinal peristalsis. Phenolphthalein can also inhibit intestinal absorption of water and electrolytes to cause defecation. The phenolphthalein-induced model has good reproducibility, and the dosage is easy to control. However, long-term use can easily lead to water and electrolyte disorders, hypoimmunity, and death in animals.
Feeding animals drug-containing diets ensures that they can freely obtain sufficient feed under conditions with limited human interference; however, it is difficult to strictly control the drug dosage administered to each animal. In contrast, intragastric administration can facilitate stricter control of the dosage and standardize the model, but also increase the influence of external factors. In addition, the method of administration may be affected by the solubility of the drug. For example, phenolphthalein is insoluble in water, but some researchers have used a phenolphthalein solution to induce a model of cathartic colon. This may have affected the effectiveness of the model. Furthermore, in many studies, the final doses of drugs are much higher than the typical clinical doses, which needs to be acknowledged.
The animals used to establish the cathartic colon model in most studies include rats, mice, and guinea pigs, among others. Rats are the first choice to establish this model. The anatomical and physiological characteristics of the rat are similar to those of humans, and it shows good adaptability to its environment, with low feeding costs. Wistar and Sprague-Dawley rats, 6-8 wk old, or 180-320 g in weight, male or female, are often used because they typically do not die easily, and yield high success rates. Mice, like rats, can be easily obtained and fed. However, compared with rats, only a few studies on cathartic colon models have used mice. Most pathological changes in cathartic colon (except melanosis coli) can be reproduced in the rat or mouse.
Guinea pigs are a little more expensive and have greater feeding requirements than rats and mice. However, melanosis coli can be easily induced in guinea pigs. This may be related to the fact that neither humans nor guinea pigs could synthesize vitamin C on their own. Most studies theorize that melanosis coli is caused by damage to the intestinal mucosa after the long-term administration of laxatives, which may lead to apoptosis of colonic epithelial cells and the formation of apoptotic bodies. Apoptotic bodies can be phagocytized by mononuclear macrophages. Under the action of lysosomes, apoptotic bodies become decomposed and produce lipofuscin, which accumulates in the lamina propria to produce melanosis coli. Interestingly, studies have shown that vitamin C protects intestinal epithelial cells from oxidant-induced apoptosis. The mechanism by which vitamin C works in response to laxative-induced melanosis coli is unclear, and warrants further investigation.