Intestinal microsomal metabolism

Intestinal microsomal metabolism can be monitored via biphenyl hydroxylation as well. Biphenyl hydroxylase assays are more sensitive than some other hydroxylase assays which has permitted measurements of the low constituative enzyme levels in intestinal mucosa and some other extrahepatic tissues (56-59) ... 

UDP-glucuronyltransferases catalyze the addition of glucuronic acid onto phenol, hydroxyl and carboxylic acid functions of molecules. They are expressed in many tissues of the body, including the liver and intestine [2-5], Microsomes from human intestines have been shown to metabolize UDP-glucuronyltransferase substrates including p-nitrophenol [6], 1-naphthol, morphine, and ethinylestradiol [4]. The relative rates of metabolism of these substrates in liver and intestinal microsomes are shown in Table 13.1. 

Esterases form a wide family of enzymes that catalyze the hydrolysis of ester bonds. They are ubiquitously expressed in all tissues including the intestine, and are found in both microsomal and cytosolic fractions. Prueksaritonont et al. [6] have studied the metabolism of both p-nitrophenol acetate and acetylsalicylic acid by esterases from human intestinal microsomal and cytosolic systems, and the activity values were 2.76 pmol min-1 mg-1 and 0.96 nmol min-1 mg-1, respectively. Thus, the activity for the hydrolysis of p-nitrophenol acetate in human intestine approaches that in the liver. 

Tab. 13.3. Relative rates metabolism in human intestinal microsomes for a series of CYP3A substrates.

The metabolism of several CYP3A4 substrates in microsomes from the upper small intestine has been compared with liver microsomal metabolism. The results are summarized in Table 13.3. Thus, microsomes from the human upper small intestine can metabolize CYP3A4 substrates at rates approaching those found in human liver microsomes. However, the rate of metabolism in intestinal microsomes can be highly variable (8-fold for sirolimus [17] and 18- to 29-fold for midazolam [19]). 

Sediments and biota collected from the Hersey River, Michigan, in 1978, were heavily contaminated with phenanthrene, benz[a]anthracene, and benzo[a]pyrene when compared to a control site. Elevated PAH concentrations were recorded in sediments, whole insect larvae, crayfish muscle, and flesh of lampreys (family Petromyzontidae), brown trout (Salmo trutta), and white suckers (Catostomus commersoni), in that general order (Black et al. 1981). The polluted collection locale was the former site of a creosote wood preservation facility between 1902 and 1949, and, at the time of the study, received Reed City wastewater treatment plant effluent, described as an oily material with a naphthalene-like odor (Black et al. 1981). In San Francisco Bay, elevated PAH concentrations in fish livers reflected elevated sediment PAH concentrations (Stehr et al. 1997). In Chesapeake Bay, spot (Leiostomus xanthurus) collected from a PAH-contaminated tributary (up to 96 mg PAHs/kg DW sediment) had elevated cytochrome P-450 and EROD activity in liver and intestine microsomes (Van Veld et al. 1990). Intestinal P-450 activity was 80 to 100 times higher in fish from highly contaminated sites than in conspecifics from reference sites intestinal EROD activity had a similar trend. Liver P-450 and EROD activity was about 8 times higher in spot from the contaminated sites when compared to the reference sites. Liver P-450 activity correlated positively with sediment PAH, but intestinal P-450 activity seemed to reflect dietary exposure (Van Veld et al. 1990). The poor correlation between hepatic concentrations of PAHs and P-4501A is attributed to the rapid metabolism of these compounds (van der Weiden et al. 1994). 

It was reported that the distribution and activities of esterases that catalyze pyrethroid metabolism using several human and rat tissues, including small intestine, liver, and serum, were examined [30]. The major esterase in human intestine was hCE2. //c/n.v-Permethrin was effectively hydrolyzed by pooled human intestinal microsomes (five individuals), while deltamethrin and bioresmethrin were not. This result correlated well with the substrate specificity of recombinant hCE2. In contrast, pooled rat intestinal microsomes (five animals) hydrolyzed trans-permethrin 4.5 times slower than the human intestinal microsomes. Furthermore, pooled samples of cytosol from human or rat liver were ca. half as hydrolytically active as the corresponding microsome fraction toward pyrethroids however, the cytosolic fractions had significant amounts (ca. 40%) of the total hydrolytic activity. Moreover, a sixfold interindividual variation in hCEl protein expression in human hepatic cytosols was observed. 

Wynalda MA, Hutzler JM, Koets MD, Podoll T, and Wienkers LC (2003) In vitro metabolism of clindamycin in human liver and intestinal microsomes. Drug Metab. Disp. 31 878-887. 

Hashizume T, Imaoka S, Mise M, Terauchi Y, Fujii T, et al. 2002. Involvement of CYP2J2 and CYP4F12 in the metabolism of ebastine in human intestinal microsomes. J Pharmacol Exp Ther 300 298-304. 

Koudriakova T, latsimirskaia E, Utkin I, et al. Metabolism of the human immunodeficiency virus protease inhibitors indinavir and ritonavir by human intestinal microsomes and expressed cytochrome P4503A4/3A5 mechanism-based inactivation of cytochrome P4503A by ritonavir. Drug Metab Dispos 1998 26(6) 552-561. 

Until recently, intestinal metabolism via CYP3A4-mediated metabolic pathways was thought to be insignificant because of the lower levels of expression compared with that seen in the liver and slower metabolic rates measured for intestinal microsomes (224). However, similar Km values have been reported for midazolam 1 -hydroxylation by microsomes obtained in the upper intestine and the liver (254,255). This correlation indicates that the upper intestine and hepatic CYP3 A4 are functionally equivalent. Such findings further establish the importance of the intestine in the elimination of orally administered substrates for CYP3 A4-mediated metabolic pathways. Additionally, coadministration of substrates/inhibitors that may alter the function of these proteins (induction, inhibition) could further be responsible for the variability in intestinal absorption (dmg interactions) seen for some dmgs. 

In vivo information on cytotoxic T-cell-suppressing agents is very limited, but men and women have not been found to have sex-dependent differences in inhibition of lymphocyte proliferation, (129). Although numerous studies have postulated the presence of sex differences based on a higher incidence of organ rejection and increased mortality in women, it is not clear that these observations are due to sex differences (130). In an in vitro study, it was found that cyclosporine was metabolized faster by small intestinal microsomes from females, but this finding was based on only four female samples (131). 

Intestinal microsomes Intestinal tissue Phase I metabolism... 

An in vitro trial of cranberry juice on human liver and rat small intestine microsomes demonstrated that cranberry juice significantly inhibited the activity of human and rat drug-metabolizing cytochrome P450 isoenzyme CYP3A... 

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