Intestinal microsomal protein

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. 

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. 

Table III, Microsomal Protein in Small Intestine Mucosa of Fiber-Fed Rats.

Table IV. Microsomal Protein in Liver and Intestinal Preparations from Fiber-Fed Rats. ...

There may be species differences in the induction of drug metabolism in extra-hepatic tissues. For example, treatment of rabbits with phenobarbital significantly increases the hydroxylation and N-demethylation of N-methylaniline and the microsomal protein and cytochrome P-4S0 content of liver and kidney microsomes, but not in lung and small intestine. However, treatment of rats with phenobarbital, 3,4-benzpyrene, or DDT does not significantly affect the levels of cytochrome P-4S0 or drug metabolism in kidney microsomes. 

In ABL, an early step in apoB lipoprotein assembly shared by intestinal and liver cells is defective. The net result is near absence of all plasma apoB lipoproteins. ApoB synthesis from a mRNA transcript occurs, but its successful assembly into the mature lipoprotein particle does not. The inability to assemble apoB into lipoproteins was shown to be due to a defect in the mttp gene in affected individuals (Wetterau et al., 1992). Its translational product is an 894-amino acid, 97-kd, polypeptide that exists in the ER complexed with a 55-kd protein disulfide isomerase which is believed to maintain solubility, physiologic activity, and ER retention of the 97-kd peptide. The heterodimeric complex of the 97-kd and 55-kd subunits is referred to as microsomal triglyceride transfer protein (MTP) (Wetterau et al., 1992). 

---