Aminotransferases resistance

All NRTIs may be associated with mitochondrial toxicity, probably owing to inhibition of mitochondrial DNA polymerase gamma. Less commonly, lactic acidosis with hepatic steatosis may occur, which can be fatal. NRTI treatment should be suspended in the setting of rapidly rising aminotransferase levels, progressive hepatomegaly, or metabolic acidosis of unknown cause. The thymidine analogues zidovudine and stavudine may be particularly associated with dyslipidemia and insulin resistance. Also,... 

The most common adverse effects of indinavir are indirect hyperbilirubinemia and nephrolithiasis due to crystallization of the drug. Nephrolithiasis can occur within days after initiating therapy, with an estimated incidence of approximately 10%. Consumption of at least 48 ounces of water daily is important to maintain adequate hydration. Thrombocytopenia, elevations of serum aminotransferase levels, nausea, diarrhea, insomnia, dry throat, dry skin, and indirect hyperbilirubinemia have also been reported. Insulin resistance may be more common with indinavir than with the other Pis, occurring in 3-5% of patients. There have also been rare cases of acute hemolytic anemia. 

Adefovir dipivoxil (Hepsera) was approved for use in chronic HBV, including lamivudine-resistant HBV, in 2002. End points of therapy for HBV include disappearance of HBV DNA and elimination of HBeAg (virologic response), resolution of elevated aminotransferases (biochemical response), and improvement of liver histology. HBeAg seroconversion, an even stricter marker of viral response, denotes the loss of both HBeAg and HBV DNA and the appearance of anti-HBe. Loss of HBsAg can occur even years after completion of therapy. 

Maximos M, Bril F, Portillo Sanchez P, Lomonaco R, Orsak B, Biernacki D, Suman A, Weber M, Cusi K (2015) The role of liver fat and insulin resistance as determinants of plasma aminotransferase elevation in nonalcoholic fatty liver disease. Hepatology 61, 153-60. 

Adefovir dipivoxil (4) was initially developed as a treatment for HIV, but the FDA in 1999 rejected the drug due to concerns about the severity and frequency of kidney toxicity when dosed at 60 or 120 mg, respectively. However, 4 was effective at a much lower dose of 10 mg for the treatment of chronic hepatitis B in adults with evidence of active viral replication and either evidence of persistent elevations in serum alanine aminotransferases (primarily ALT) or histologically active disease. It works by blocking reverse transcriptase, an enzyme that is crucial for the HBV to reproduce in the body. Overall, the efficacy of 4 against wild-type and lamivudine (2)-resistant HBV and the delayed emergence of 4-resistance during monotherapy contribute to the durable safety and efficacy observed in a wide range of chronic hepatitis B patients. ... 

Liver The most common laboratory abnormalities observed in the RESIST trials were raised aminotransferase activities [203, 204, 205 ]. Susceptibility factors included infection with hepatitis B or C and high baseline aminotransferases. 

Albendazole 10 mg/kg/day has been used to treat cystic echinococcosis (hydatid disease) in 11 children aged 4—14 years, with at least 10 cysts in the same organ [8 ]. The children had a total of 296 cysts located mostly in the liver (178 cysts) and the lungs (78 cysts). With exclusive albendazole therapy, 58% of pulmonary cysts, 96% of peritoneal cysts, but only 32% of hepatic cysts were cured. There were no adverse events related to treatment, apart from slight rises in serum aminotransferase activities in two cases, which normalized without withdrawal of albendazole. The high rate of viable cysts after medical therapy is problematic and in this case was attributed to poor diffusion of albendazole into the cysts, because of their multiplicity and contiguity, variable sensitivity of each cyst to albendazole, and/or insufficient duration of treatment resistance to albendazole was unlikely. 

From this list it is evident that the process economy for the production of a desired chiral amine could be improved if the aminotransferase is engineered toward amine donor resistance, temperature resistance, and high activity. These can be achieved by enzyme engineering [1,16,20-24,30]. 

Use of enrichment culture for directed evolution of the Vibriofluvialis JS17 (D-aminotransferase, which is resistant to product inhibition by aliphatic ketones. Appl. Environ. Microbiol., 71, 4220-4224. 

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