Current Pharmaceutical Biotechnology - Volume 4, Issue 3, 2003

This review describes microbial transformation studies of natural drugs, its importance in correlating them with the corresponding metabolism (biotransformation) in animal system and in the structural modification of complex drug molecules, which are difficult to obtain synthetically. Emphasis is laid on the potential microorganisms, which mimic the pathways of mammalian metabolism and which involve in stereoselective, regiospecific and selective conversions of natural drugs to their derivatives by microorganisms, which are more useful and difficult to synthesize. This paper describes the present state-of-art, will elucidate the additional possibilities with microbial biotransformation of natural drugs, i.e., comparison of microbial transformation with mammalian metabolism and possibility of producing novel molecules, which are difficult to produce by other means.

Infection with human hepatitis C virus (HCV) as a result of a bilateral process of host-virus interactions. There are factors on both sides that contribute to clearance and to chronicity. Virus strategy to survive is built on several basic features. The first, recently recognized, is a wide cell tropism. HCV can infect not only hepatocytes, but also cells of immune system (B-cells, monocytes, macrophages, dendritic cells), epithelium, and immunologically privileged sites such as the central nervous system. Dendritic cells and platelets can also be passive virus carriers. Possibilities of virus clearance or abortive inapparent HCV infection at the stage of adsorption are considered. The second feature is rapid error-prone replication that leads to accumulation within one host of multiple virus variants (quasispecies). Viral heterogeneity could be multiplied by recombination of HCV genomic / subgenomic RNA molecules. Quasispecies nature gives virus an advantage in adaptation to varying host environment including availability of permissive cells, the presence of innate and adaptive immune response, and antiviral treatment. Analysis of HCV polymorphisms and their evolution rates may pinpoint the molecular (sequence) correlates of HCV clearance. The third feature is the capacity to modify or adapt host milieu. HCV core, envelope E2 and nonstructural NS2, NS3, NS5A proteins seem to hold a grip over the host cellular functions by down-regulating processes unfavorable and up-regulating processes favorable for virus replication and persistence. The relevance of the latter interactions to HCV infection outcome remains to be demonstrated. This review discusses recent developments in this area of HCV research. (248 words)

This review is an attempt to characterize the host in the earliest events of hepatitis C virus (HCV) infection before the on-set of adaptive immune response. Host meets the replicating HCV with innate immune response in the form of proinflammatory cytokine production, activation of natural killer (NK), NKT and dendritic cells. The potency of innate response is shaped by a wide panel of genetically predetermined constants and acquired variables. Higher rates of HCV clearance associate with white ethnicity and certain HLA haplotypes. Lower clearance rates correlate with genetic immune deficiencies / disorders. Recent findings link infection outcome with variation in the genes for the low-density lipoprotein and complement type 1 receptors. Important though insufficiently characterized is the role of polymorphisms in the genes responsible for induction of antiviral immunity. The outcome of HCV entry and of subsequent acute infection (if that occurs) is pre-determined by the immune competence of the host at the moment of infection. Higher rate of HCV clearance is observed for pediatric patients and young adults. Bad prognostic markers would be post-transplantation immune suppression, transfusion-related immune modulation, alcohol-induced immune imbalance and intoxication. Among host variables is the immune modulation induced by parasitic and viral co-infections. Some of the variables are transient and hard to define in retrospective. These host characteristics set up the potency, kinetics, and profile (Th1 / Th2) of subsequent adaptive immune response. Better understanding of the host correlates of viral clearance would be a step towards prophylaxis of infection and an efficient anti-HCV vaccine.

Chronic hepatitis C virus (HCV) infection results in the development of liver fibrosis and cirrhosis in 20 to 25% of patients. The main task of the physician when examining a patient with a verified HCV infection is to identify the activity of inflammatory and necrotic processes in the liver, as well as the stage of fibrosis, and the reversibility of detected changes. Along with other clinical and laboratory parameters, this plays a major role in forecasting the course of hepatitis, as well as determines the therapeutic approach in each specific case. Liver biopsy remains the best way to assess the severity of chronic hepatitis C. The risk of developing cirrhosis depends on the stage (degree of fibrosis) and the grade (degree of inflammation and necrosis) observed in the initial liver biopsy. Non-invasive diagnostic approaches attempt to evaluate the serum markers of fibrogenesis. Biochemical markers of fibrosis scoring include thrombocyte counts, the prothrombin time, ratio of alaninaminotransferase (ALT) and aspartataminotransferase (AST) levels, the level of gglutamyl transferase and the quantity of blood serum albumin. Another set of markers is based on the detection of molecular junctions that activate fibrosis, or participate in the generation of the liver extracellular matrix. The most applicable include hyaluronic acid (HA), type IV collagen (IV-C), N-terminal propeptide of type III procollagen (PIIIP), metalloproteinases (MMP), inhibitors of metalloproteinases (TIMP), and growth-transforming factor betta (GTFbeta). The review discusses the clinical significance of each of the criteria and possibility of their combination in the non-invasive monitoring of liver fibrosis. (250 words)

Carnitine is an ammo acid derivative found in high energy demanding tissues (skeletal muscles, myocardium, the liver and the suprarenal glands). It is essential for the intermediary metabolism of fatty acids. Carnitine is indispensable for β-oxidation of long-chain fatty acids in the mitochondria but also regulates CoA concentration and removal of the produced acyl groups. AcylCoAs act as restraining factor for several enzymes participating in intermediary metabolism. Transformation of AcylCoA into acylcarnitine is an important system for removing the toxic acyl groups.Although primary deficiency is unusual, depletion due to secondary causes, such as a disease or a medication side effect, can occur. Primary carnitine deficiency is caused by a defect in plasma membrane carnitine transporter in muscle and kidneys. Secondary carnitine deficiency is associated with several inborn errors of metabolism and acquired medical or iatrogenic conditions, for example in patients under valproate and zidovuline treatment. In cirrhosis and chronic renal failure, carnitine biosynthesis is impaired or carnitine is lost during hemodialysis.Other chronic conditions like diabetes mellitus, heart failure, Alzheimer disease may cause carnitine deficiency also observed in conditions with increased catabolism as in critical illness. Preterm neonates develop carnitine deficiency due to impaired proximal renal tubule carnitine re-absorption and immature carnitine biosynthesis.Carnitine stabilizes the cellular membrane and raises red blood cell osmotic resistance but has no metabolic influence on lipids in dialysis patients. L-Carnitine has been administered in senile dementia, metabolic nerve diseases, in HIV infection, tuberculosis, myopathies, cardiomyopathies, renal failure anemia and included in baby foods and milk.