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Biotransformation of xenobiotics in human intestinal mucosa
Abstract:
Drug-metabolizing enzymes, especially monooxygenases, play a major role in biotransformation and detoxification of many foreign compounds including environmental carcinogens. Although largely localized in the liver they are also found in the small intestine, which is the portal of entry of dietary toxins. Therefore cytochrome P-450 content as well as monooxygenase (7-ethoxycoumarin O-deethylase) and NADPH-cytochrome c reductase activities were determined in surgical specimens of the human small intestine and in jejunal biopsy material obtained from patients by use of a hydraulic biopsy instrument. Microsomes were prepared from surgical material; these ranged in P-450 content from 30 to 120 pmole/mg protein and in monooxygenase activity from 60 to 110 pmole/min-mg protein. In the 20,000g supernatant of the homogenized biopsy material, monooxygenase activity was undetectable in patients who had total villous atrophy, and low enzyme rates were found when the mucosa showed a partial villous atrophy. The mucosal monooxygenase activity of patients with normal jejunal histology and steatorrhea was significantly higher than in mucosa with villous atrophy but was only half of that observed in normal controls. These eight control patients had normal histology and no malassimilation. Our results suggest that monooxygenase activity in the human small intestine is dependent on the morphological integrity of the mucosa and that in normal mucosa the enzyme rates are reduced when malassimilation is present.
Insights
Drug-metabolizing monooxygenase activity in the small intestine is crucial for detoxifying harmful compounds. This activity depends on the small intestine
Area of Science:
- Pharmacology
- Gastroenterology
- Biochemistry
Background:
- Drug-metabolizing enzymes, particularly monooxygenases, are vital for biotransformation and detoxification of foreign compounds.
- The small intestine, a primary entry point for dietary toxins, also harbors these enzymes, alongside the liver.
Purpose of the Study:
- To quantify cytochrome P-450 content and monooxygenase (7-ethoxycoumarin O-deethylase) and NADPH-cytochrome c reductase activities in the human small intestine.
- To investigate the relationship between mucosal morphology and enzyme activity in the jejunum.
Main Methods:
- Enzyme activities and P-450 content were measured in microsomes from surgical specimens of the human small intestine.
- Jejunal biopsy material from patients was analyzed using a hydraulic biopsy instrument.
- Monooxygenase activity was assessed in relation to jejunal histology (total villous atrophy, partial villous atrophy, normal histology) and clinical conditions (steatorrhea, malassimilation).
Main Results:
- Surgical specimens showed a range of P-450 content (30-120 pmole/mg protein) and monooxygenase activity (60-110 pmole/min-mg protein).
- In biopsy material, monooxygenase activity was undetectable in total villous atrophy and low in partial villous atrophy.
- Mucosal monooxygenase activity was significantly reduced in patients with villous atrophy and also in those with normal histology but steatorrhea, compared to normal controls.
Conclusions:
- Small intestinal monooxygenase activity is contingent upon the morphological integrity of the jejunal mucosa.
- Reduced enzyme rates in normal mucosa with malassimilation suggest impaired detoxification capacity.
- These findings highlight the importance of mucosal health for effective xenobiotic metabolism in the small intestine.