Microsomal activities, extrahepatic

Oral or parenteral administration of phenobarbital can increase the cytosolic CarbE activity more than the microsomal activity, and the activity can remain elevated for 7 days after the last phenobarbital treatment. Phenobarbital treatment has no effect on the extrahepatic CarbE activity. 

Drug-induced inhibition of microsomal and extrahepatic enzyme systems, such as MAO, will be predictably responsible for clinically significant interactions. Because of decreased metabolic activity, more unmetabolized drug will be in circulation, resulting in prolonged and sometimes greatly increased pharmacological activity. 

Factors other than cytochrome P-450 also could be responsible for differences in extrahepatic vrs hepatic microsomal activities involved in IPO metabolism. For example, one experiment that suggested this showed that an antibody prepared against purified cytochrome b5 almost completely inhibited the metabolism of IPO by rat pulmonary microsomes, but it had little effect on IPO metabolism by rat hepatic microsomes(28). 

Evidence suggests that endosulfan can induce microsomal enzyme activity. Increased liver microsomal cytochrome P-450 activity was observed in male and female rats after single and multiple administrations of endosulfan (Siddiqui et al. 1987a Tyagi et al. 1984). Increased enzyme activity was observed in hepatic and extrahepatic tissues. Based on the increase in aminopyrine-A-demethylase and aniline hydroxylase activity, endosulfan has been shown to be a nonspecific inducer of drug metabolism (Agarwal et al. 1978). 

LC/MS/MS with selected reaction monitoring (SRM) offers a fast and simple means to analyze biological matrices, which is a key factor in high-throughput CYP inhibition screens using liver microsomes. Potentially, the LC/MS/MS technique is suitable for analyses of cocktail substrates in other in vitro drug metabolism evaluations such as CYP induction/activation assays, rapid analysis of pooled liver microsomes, rapid reaction phenotyping of tissue (hepatic and extrahepatic) samples, as well as evaluation of hepatocytes/tissue slice CYP activity. ° ... 

Clement B, Mau S, Deters S, et al. Hepatic, extrahepatic, microsomal, and mitochondrial activation of the n-hydroxylated prodrags benzamidoxime, guanox-abenz, and RO 48-3656 ([[l-[(2S)-2-[[4-[(hydroxyamino)iminomethyl]benzoyl] amino]-l-oxopropyl]-4-piperidinyl]oxy]-acetic acid). Drag Metab Dispos 2005 33 1740-1747. 

Menaquinones are synthesized by intestinal bacteria, but it is unclear how much they contribute to vitamin K nutrition, because they are extremely hydrophobic, and win only be absorbed from regions of the gastrointestinal tract where bUe salts are present - mainly the terminal Ueum. However, prolonged use of antibiotics can lead to vitamin K deficiency and the development of vitamin K-responsive hypoprothrombinemia (Section 5.4), as can dietary deprivation of phylloquinone. In vitro, menaquinones 2 to 6 have the same activity as phylloquinone as coenzyme for the solubilized liver microsomal vitamin K-dependent carboxylase (Section 5.3.1), whereas menaquinones with a side chain longer than seven have lower activity (Suttie, 1995). In extrahepatic tissues, the principal active vitamer is menaquinone-4 (Thijssen and Drittij-Reijnders, 1996 Thijssen et al., 1996). 

Hepatic and extrahepatic CarbE activities have been studied after the exposure of rats to polycyclic aromatic hydrocarbons. In dose- and time-dependent studies, benz(a)anthracene, benzo(a)pyrene, and 3-methylcholanthrene moderately induced the hepatic cytosolic and kidney microsomal CarbEs activities, while anthracene, phenanthrene, and chrysene had... 

DePierre, J. W., Seidegard, J., Morgenstern, R., Balk, L., Meijer, J., Astrom, A., Norelius, I., and Ernster, L. (1984) Induction of cytosolic glutathione transferase and microsomal epoxide hydrolase activities in extrahepatic organs of the rat by phenobarbi-tal, 3-methylcholanthrene and trans-stilbene oxide. Xenobiotica 14, 295-301. 

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