Tissues, extrahepatic

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). 

In the liver, its major function is to ptovide glucose for extrahepatic tissues. In muscle, it setves mainly as a ready source of metabolic fuel fot use in muscle. 

In extrahepatic tissues, hexokinase catalyzes the phosphorylation of most hexose sugars, including fruc-... 

Ketone Bodies Serve as a Fuel for Extrahepatic Tissues... 

In extrahepatic tissues, acetoacetate is activated to acetoacetyl-CoA by succinyl-CoA-acetoacetate CoA transferase. CoA is transferred from succinyl-CoA to form acetoacetyl-CoA (Figure 22-8). The acetoacetyl-CoA is split to acetyl-CoA by thiolase and oxidized in the citric acid cycle. If the blood level is raised, oxidation of ketone bodies increases until, at a concentration of approximately 12 mmol/L, they saturate the oxidative machinery. When this occurs, a large proportion of the oxygen consumption may be accounted for by the oxidation of ketone bodies. 

In most cases, ketonemia is due to increased production of ketone bodies by the liver rather than to a deficiency in their utilization by extrahepatic tissues. While acetoacetate and d(—)-3-hydroxybutyrate are readily oxidized by extrahepatic tissues, acetone is difficult to oxidize in vivo and to a large extent is volatilized in the lungs. 

Figure 22-8. Transport of ketone bodies from the liver and pathways of utilization and oxidation in extrahepatic tissues.

Ketone bodies are important fuels in extrahepatic tissues. 

The clearance of labeled chylomicrons from the blood is rapid, the half-time of disappearance being under 1 hour in humans. Larger particles are catabolized more quickly than smaller ones. Fatty acids originating from chylomicron triacylglycerol are delivered mainly to adipose tissue, heart, and muscle (80%), while about 20% goes to the liver. However, the liver does not metabolize native chylomicrons or VLDL significantly thus, the fatty acids in the liver must be secondary to their metabolism in extrahepatic tissues. 

The hver and many extrahepatic tissues express the LDL (B-lOO, E) receptor. It is so designated because it is specific for apo B-IOO but not B-48, which lacks the carboxyl terminal domain of B-lOO containing the LDL receptor ligand, and it also takes up lipoproteins rich in apo E. This receptor is defective in familial hypercholesterolemia. Approximately 30% of LDL is de-... 

The reason for the cholesterol-lowering effect of polyunsaturated fatty acids is still not fully understood. It is clear, however, that one of the mechanisms involved is the up-regulation of LDL receptors by poly-and monounsaturated as compared with saturated fatty acids, causing an increase in the catabolic rate of LDL, the main atherogenic lipoprotein. In addition, saturated fatty acids cause the formation of smaller VLDL particles that contain relatively more cholesterol, and they are utilized by extrahepatic tissues at a slower rate than are larger particles—tendencies that may be regarded as atherogenic. 

Figure 27-1. Metabolic interrelationships between adipose tissue, the liver, and extrahepatic tissues. In extrahepatic tissues such as heart, metabolic fuels are oxidized in the following order of preference (1) ketone bodies, (2) fatty acids, (3) glucose. (LPL, lipoprotein lipase FFA, free fatty acids VLDL, very low density lipoproteins.)...

Both intact carotenoids and their apolar metabolites (retinyl esters) are secreted into the lymphatic system associated with CMs. In the blood circulation, CM particles undergo lipolysis, catalyzed by a lipoprotein lipase, resulting in the formation of CM remnants that are quickly taken up by the liver. In the liver, the remnant-associated carotenoid can be either (1) metabolized into vitamin A and other metabolites, (2) stored, (3) secreted with the bile, or (4) repackaged and released with VLDL particles. In the bloodstream, VLDLs are transformed to LDLs, and then HDLs by delipidation and the carotenoids associated with the lipoprotein particles are finally distributed to extrahepatic tissues (Figure 3.2.2). Time-course studies focusing on carotenoid appearances in different lipoprotein fractions after ingestion showed that CM carotenoid levels peak early (4 to 8 hr) whereas LDL and HDL carotenoid levels reach peaks later (16 to 24 hr). 

P. H., Cytochrome P 450 isoenzymes, epoxide hydrolase and glutathione transferases in rat and human hepatic and extrahepatic tissues, J. Pharmacol. Exp. Ther. 1990, 253, 387-394. 

Al-Bayati, Z.A.F., W.J. Murray, and S.J. Stohs. 1987. 2,3,7,8-,l etrachlorodibenzo-/)-dioxin-induced lipid peroxidation in hepatic and extrahepatic tissues of male and female rats. Arch. Environ. Contam. Toxicol. 16 159-166. 

Data suggest that extrahepatic tissue (i.e., the immune system) may also play an important role in the in situ biotransformation of xenobiotics, such as polycyclic aromatic... 

Crosbie SJ, Blain PG, Williams FM. 1997. Metabolism of -hexane by rat liver and extrahepatic tissues and the effect of cytochrome P-450 inducers. Hum Exp Toxicol 16 131-137. 

CYP2B6. While generally accounting for significantly less then 1% of the total P450 present in human liver, CYP2B6 is also found in extrahepatic tissue, including... 

Sucdnyl CoA is a high-energy intermediate that can be used for heme synthesis and to activate ketone bodies in extrahepatic tissues. 

Acetoacetate picked up from the blood is activated in the mitochondria by succinyl CoA ace-toacetyl CoA transferase (common name thiophorase), an enzyme present only in extrahepatic tissues 3-hydroxybutyrate is first oxidized to acetoacetate. Because the liver lacks this enzyme, it carmot metabolize the ketone bodies. 

The liver requires cholesterol for synthesizing VLDL particles and bile acids. Triglyceride-rich VLDL particles are released into the blood and, like the chylomicrons, supply other tissues with fatty acids. Left behind are LDL particles that either return into the liver or supply extrahepatic tissues with cholesterol. 

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