Secondary metabolites glutathione conjugates

Figure 1.4 Compaitmentation of biosynthesis and sequestration. Abbreviations SM, secondary metabolites CS-SM, conjugate of SM with glutathione NPAAs, non-protein amino acids ATP, adenosine triphosphate ADP, adenosine diphosphate mt, mitochondrion cp, chloroplast nc, nucleus 1, passive transport 2, free diffusion 3, H+/SM antiporter 4, ABC transporter for SM conjugated with glutathione 5, ABC transporter for free SM 6, H+-ATPase. (See Plate 3 in colour plate section.)...

Medications in this class include delavirdine, efa-virenz, and nevirapine. Similar to the NRTls, these agents bind to viral reverse transcriptase and block DNA polymerase activity. A key difference is that NNRTIs do not require intracellular phosphorylation and are not incorporated into viral DNA. Clinically significant kidney toxicities or specific fluid-electrolyte complications have not been reported with this class of agents. In the rat model, efavirenz was associated wifh a species specific dependent kidney toxicity which occurred secondary to the development of a unique glutathione conjugate produced as a metabolite of efavirenz associated with renal tubular epifhelial cell necrosis [125-126]. This toxicity has not been observed in humans. One patient was recently reported to have reversible nephrotic-range proteinuria attributed to efavirenz use, in which a kidney biopsy showed diffuse podocyte foot process effacement [127]. Another report noted the development of rhabdomyolysis and acute tubular necrosis as a result of a drug interaction between delavirdine and atorvastatin [128]. Kidney toxicity due to nevirapine has not been reported. 

The herbicide alachlor (4.146, Fig. 4.7) also displayed species-dependent toxicity, since it induced nasal tumors in rats but not in mice. Its metabolic scheme in rats and mice (Fig. 4.7) shows that alachlor can be transformed into 2,6-diethylaniline (4.149) by two different pathways, one of which proceeds via formation of 4.147. The other pathway implies glutathione (GSH) conjugation, followed by /3-lyase-mediated liberation of the thiol, followed by S-methylation to produce the methylsulfide 4.148. The two secondary amides 4.147 and 4.148 were hydrolyzed by microsomal arylamidases, but alachlor itself was not a substrate for this enzyme. The hydrolytic product 2,6-diethylaniline (4.149) was oxidized in nasal tissues to the electrophilic quinonimine metabolite 4.150, which can bind covalently to proteins. Aryl-... 

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