Liver inhibitor binding

In order to give useful information about an enzyme, a conformationally restricted active-site-directed analog inhibitor need not bind to the enzyme irreversibly. In a study of the enzyme fructose 1,6-diphosphatase from rabbit liver, Benkovic et al, have investigated the question of the reactive form of the fructose 1,6-diphosphate in the enzymatic process (104,105). Three likely forms are shown in structures 50, 51 and 52. 

Avallone R, Zeneroli ML, Venturini I, Corsi L, Schreier P, Kleinschnitz M, Ferrarese C, Farina F, Baraldi C, Pecora N, Frigo M, Baraldi M Endogenous benzodiazepine-like compounds and diazepam binding inhibitor in serum of liver cirrhosis patients with and without encephalopathy. Gut 1998 42 860-867. 

Naerum, L. Norskov-Lauridsen, P. B. Rasmussen, L. Thim, F. C. Wiberg, and K. Lundgren, Characterization of the allosteric binding pocket of human liver fructose 1,6-bisphosphatase by protein crystallography and inhibitor activity studies, Protein Sci. 6 971 (1997). 

Elevated metallothionein levels are not necessarily indicative of heavy-metal insult. Starcher et al. (1980) show that liver metallothionein levels in mice are elevated following acute stress or starvation, and that this effect is blocked by actinomycin D, a protein synthesis inhibitor. It is further emphasized that not all zinc-binding proteins are metallothioneins (Webb etal. 1985 ... 

In contrast to P-gp and the MRP proteins, the breast cancer resistance protein (BCRP) contains six transmembrane domains and only one ATP-binding domain. It was first cloned from the breast cancer cell line MCF-7 selected in doxombicin, in the presence of the P-gp inhibitor verapamil. It is found in many human tissues, such as the placenta, small intestine, colon, and liver [133], It is localized to the apical membrane of epithelial cells of the small intestine and colon and to the bile canalicular membrane in the liver and is involved in reducing intestinal uptake, increasing hepatobiliary excretion, etc., leading to diminished oral bioavailability. cDNA sequences identical to BCRP and named MXR and ABCP, respectively, were independently isolated from human colon carcinoma cells and human placenta [134], BCRP requires... 

Another drug with a high incidence of hepatotoxicity is the acetylcholinesterase inhibitor tacrine. Binding of reactive metabolites to liver tissue correlated with the formation of a 7-hydroxy metabolite [13], highly suggestive of a quinone imine metabolite as the reactive species. Such a metabolite would be formed by further oxidation of 7-hydroxy tacrine (Figure 8.11). 

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