Renal enzyme processes

Overall, the kidney is highly susceptible to the toxicity of hexachlorobutadiene, in contrast to other organs, due to the activity of p-lyase and other mercapturic acid processing enzymes (Vamvakas et al. 1988b). The greater sensitivity of females may be due to differences in renal enzymes responsible for the tissue levels of the active metabolites (Hook et al. 1983). Based on data in animals, renal toxicity is a major concern in humans who may be chronically exposed to this material from hazardous waste sites or other sources. 

Results on operational stability of both acylases in a recycle reactor at constant conversion1641 with reaction conditions close to intended large-scale conditions demonstrated much better stability of the Aspergillus enzyme, while renal enzyme is not stable enough for long-term operation164,651. Moreover, on the process scale achieved today the supply of renal acylase is insufficient, so that fungal acylase is used almost exclusively nowadays, especially since the price per unit is comparable. 

When considering the mechanism by which drug causes nephrotoxicity, two components of renal function are decisive. The first are the renal transport processes which are critical to recovering essential minerals and nutrients from the glomerular filtrate and the second are the renal enzyme systems which are essential to both detoxification of xenobiotics and maintaining the bod)/ s acid/base homeostasis [22, 23]. 

After production in the liver, 25-OHD enters the circulation, largely bound by vitamin D-binding protein. Final activation occurs predominantly in the kidney, where la-hydroxylase in the proximal tubule converts 25-OHD to calcitriol. This process is highly regulated (Figure 61—5). Calcitriol and 25-OHD also can be hydroxylated by another renal enzyme, 24-hydroxylase, to make compounds that have considerably lower biological activity and presumably are destined for excretion. 

In the light of the available evidence one might be tempted to accept the theory of the renal origin of hypertension and to visualize perhaps a disturbance in the balance between these two enzymic processes as the driving force behind a vicious circle of pathological events. However, the following discussion will show that the problem of the pathogenesis of hypertension has not yet been solved. 

Other- Liver disease with impaired hemostasis severe renal disease. Hyperlipidemia Heparin may increase free fatty acid serum levels by induction of lipoprotein lipase. The catabolism of serum lipoproteins by this enzyme produces lipid fragments that are rapidly processed by the liver. Patients with dysbetalipoproteinemia (type III) are unable to catabolize the lipid fragments, resulting in hyperlipidemia. 

Unlike renal function, hepatic maturation is generally believed to be a two-stage process with the major development completed at 4 weeks postpartum and tlie second stage completed by about 10 weeks of age. In sheep, for example, tlie activity of a number of hepatic drug-metabolizing enzymes was found to be relatively low in animals aged up to 6 months compared with adult individuals... 

If the (3-lyase enzyme, or the renal basolateral membrane transport system, or y-glutamyltransferase, or cysteinylglycinase is inhibited, the nephrotoxicity of DCVC can be reduced, indicating that each of these processes is involved. 

Figure 7.33 The renal accumulation and toxicity of gentamycin (G). Gentamycin is filtered in the glomerulus and enters the tubular lumen. Here, it is taken up by proximal tubular cells and in vesicles as part of the uptake process. These fuse with lysosomes (L) inside the cell. The accumulation of gentamycin inside the lysosome destabilizes it, causing it to rupture and release its hydrolytic enzymes (o). These cause damage within the cell. Also, gentamycin can directly damage mitochondria (M).

Whatever the site of the enzyme may be, Keston et al. have recently produced fairly conclusive evidence that glucose, which is reabsorbed by the kidney, is exposed to mutarotase at some stage of the process (117). Glucose infused into the renal artery spills into urine when the renal threshold is exceeded in the same anomeric form as that administered, whereas reabsorbed glucose in the renal vein is mutarotated. Hill has also shown that the anomer infused in excess is excreted in excess (73). 

From either a Cp or In Cp versus time plot, one feature is immediately clear the drug concentration drops over time. This process is called elimination and is determined by clearance (CL). Clearance is the process of removal of drug from the bloodstream. As was discussed in Chapter 3, clearance occurs primarily either through filtration of a drug by the kidneys (renal clearance, CLR) or metabolism of a drug in the liver by the action of enzymes (hepatic clearance, CLH). Other clearance processes are possible, but CLR and CLh normally comprise the large majority of total clearance (CLy or simply CL) (Equation 7.6). 

If the rate of elimination decreases in Scheme 7.2, then what happens to clearance Clearance is unchanged. For each 4.0-second pass, the liver clears 50 mL (CLh = 12.5 mL/s) out of the total 100 mL of blood that flows through the organ. Literally, 50% of the blood volume is cleared, so the actual impact is a decrease in Cp by 50%. While clearance is constant, the effect of clearance on Cp varies with Cp. Clearance depends on the action of metabolic enzymes on the drug and, at very high drug concentrations, the enzymes can become saturated with substrate. Under these conditions, which are rare, clearance is not constant. Therapeutic concentrations of modem drugs are normally well below the concentrations required to saturate liver enzymes. The tubular secretion and reabsorption processes in the kidneys can also be saturated and affect renal clearance. As with hepatic clearance, variable renal clearance is rare. 

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