Cytosol resistance

Several groups of drugs that bind to tubulin at different sites interfere with its polymerization into microtubules. These drugs are of experimental and clinical importance (Bershadsky and Vasiliev, 1988). For example, colchicine, an alkaloid derived from the meadow saffron plant Colchicum autumnale or Colchicum speciosum), is the oldest and most widely studied of these drugs. It forms a molecular complex with tubulin in the cytosol pool and prevents its polymerization into microtubules. Other substances such as colcemid, podophyllotoxin, and noco-dazole bind to the tubulin molecule at the same site as colchicine and produce a similar effect, albeit with some kinetic differences. Mature ciliary microtubules are resistant to colchicine, whereas those of the mitotic spindle are very sensitive. Colchicine and colcemid block cell division in metaphase and are widely used in cytogenetic studies of cultured cells to enhance the yield of metaphase plate chromosomes. 

Tsukamoto N, Chen J, Yoshida A. Enhanced expressions of glucose-6-phos-phate dehydrogenase and cytosolic aldehyde dehydrogenase and elevation of reduced glutathione level in cyclophosphamide-resistant human leukemia cells. Blood Cells Mol Dis 1998 24 231-238. 

To date, 16 GST isozymes have been found in humans [48]. Studies of several cancer tissues have revealed the overexpression of different GST isozymes, with GST Pl-1 (GST Pi, GST ji) being the most predominant. For this reason, GST Pl-1 is regarded as a potential tumor marker [5,49-53]. The high expression levels of GST Pl-1 (up to 2.7% of the total cytosolic protein [52]), combined with its detoxification role against xenobiotics, make GST Pl-1 a major player responsible for drug resistance in patients undergoing anticancer chemotherapy [49]. 

Gorodeski GI, Hopfer U, and Wenwu J [1998] Purinergic receptor induced changes in paracellular resistance across cultures of human cervical cells are mediated by two distinct cytosolic calcium related mechanisms. Cell Biochem Biophys 29 281-306... 

An unusual case of intramolecular competition (chemoselectivity, see Chapt. 1 in [la]) between ester and oxirane occurs in the detoxification of (oxiran-2-yl)methyl 2-ethyl-2,5-dimethylhexanoate (10.49), one of the most abundant isomers of an epoxy resin. The compound is chemically very stable, i.e., resistant to aqueous hydrolysis, but is rapidly hydrolyzed in cytosolic and microsomal preparations by epoxide hydrolase and carboxylesterase, which attack the epoxide and ester groups, respectively [129], The rate of overall enzymatic hydrolysis was species dependent, decreasing in the order mouse > rat > human, but was relatively fast in all tissues examined (lung and skin as portals of entry, and liver as a further barrier). In mouse and rat lung microsomes, ester hydrolysis was 3-4 times faster than epoxide hydration, whereas the opposite was true in human lung microsomes. 

Although extensive biochemical data on both the bacterial and eukaryotic ATP-dependent proteases are available, the characterization of these proteolytic machines at atomic resolution has proven difficult, because of both the large size of these complexes and their lability to proteolysis and dissociation. No structural data at all are currently available for Lon and the mitochondrial ATP-dependent proteases. In the case of the cytosolic, membrane-integrated bacterial protease FtsH, atomic resolution data are available only for the ATPase domain (Krzywda et al. 2002 Niwa et al. 2002). In contrast, the ATP-dependent activators of the ClpAP and ClpXP proteolytic machines have so far resisted crystallization. Atomic resolution data are available only for the proteolytic component ClpP (Wang et al. 1997), and separately for a ClpX monomer (Kim and Kim 2003) and a ClpA monomer (Guo et al. 2002b). 

Leach KL, James ML, Blumberg PM (1983) Characterization of a specific phorbol ester aporeceptor in moujse brain cytosol. Proc Natl Acad Sci USA 80 4208-4212 Lee SA, Karaszkiewicz JW, Anderson WB (1992) Elevated level of nuclear protein kinase C in multidrug-resistant MCF-7 human breast carcinoma cells. Cancer Res 52 3750-3759... 

Two other common mechanisms of resistance are known. Some cases of resistance of aerobic gramnegative bacilli to streptomycin are due to mutations in the proteins of the bacterial ribosomes. Streptococci, staphylococci, and Pseudomonadaceae resist aminoglycosides as a result of decreased transport of the aminoglycosides into the bacterial cytosol. 

Anaerobes also are resistant to aminoglycosides because of decreased transport into the bacterial cytosol. Combining an aminoglycoside with an antibiotic that disrupts the bacterial cell wall can overcome this natural resistance. 

Perez-Victoria, J.M. et al.. Correlation between the affinity of flavonoids binding to the cytosolic site of Leishmania tropica multidrug transporter and their efficiency to revert parasite resistance to daunomycin. Biochemistry, 38, 1736, 1999. 

---