Enzymes - continued adaptation

MEGX is readily detected by HPLC and fluorescence polarization immunoassay techniques [14,21,25,40,41]. The test is simple, normally requiring a onetime blood sampling, and informative because it depends on the capacity of the hepatic enzymes to metabolize lidocaine. While the analysis of lidocaine metabolites is rapid, this method has not been adapted for continuous hepatic function monitoring, which may be possible with the radiolabeled analogues such as Tc-Sn-lidocaine iminodiacetic acid [42]. 

FIGURE 11.8 Ambient H202 concentrations measured by TDLS ( ) and the continuous scrubbing enzyme fluorometric technique ( ) during the period June 24-26 at Research Triangle Park, North Carolina (adapted from Schiff et al., 1994a, 1994b). 

There is no dearth of chemical compounds that will cause a rise in blood pressure when injected into the experimental animal. Extracts of plant and animal tissues yield several, and enzymes present in the tissues will often produce pressor substances as a result of autolysis. For a chemical agent then to be proved as a cause of hypertension it must be found as such in the animal and in greater amount in the hypertensive than in the normal animal. The substance must be capable of producing a continued elevation of blood pressure when administered continuously to the normal animal. The substance must be of such a nature that the body does not make corrective or adaptive responses to it. In this fashion tachyphylaxis or immunological reactions may reduce the action of certain agents if given repeatedly. 

The course of the isomerization reaction observed in a suspension of the fixed isomerase in D-glucose solution is translatable to the degree of isomerization attainable as a function of the rate of flow of the substrate through a bed of the fixed isomerase. In adapting the rate expressions 4 and 6 to a reactor in which substrate flows continuously through a bed of fixed enzyme, the factor t expresses the ratio of the volume of substrate in contact with enzyme in the reactor to the volumetric rate of flow. 

In general, the fixed D-glucose isomerase systems have many advantages with respect to enzyme use, efficiency, ease of handling, and adaptability to continuous-reactor operation. Methods have been described that employ a continuously stirred tank-reactor provided with a semipermeable membrane through which the isomerized liquor, having the steady-state composition, is removed from the reaction medium at the same rate as fresh substrate is introduced into the reactor.47 The soluble enzyme is retained in the reaction zone, because it is held back by the semipermeable membrane, and fresh enzyme may be added as needed, to compensate for enzyme inactivation, to the reaction zone with the fresh substrate. 

Surprisingly, individuals with hemoglobin levels as low as 20 to 30 mg Hb/ml can continue to be physically active. This is due to adaptive mechanisms involving an increase in the heart rate and an increase in efficiency of extraction of oxygen from the blood. Experiments with rats have revealed that the decreased work capacity of the iron-deficient animals, as determined by their ability to run, was due to a deficiency in the enzymes of the respiratory chain of muscle, as well as to anemia. In short, transfusion with normal blood failed to restore fully the running capacity of the deficient animals. 

Still another possibility has been discussed by Scriver (S8, S9). Two assumptions are necessary. The first is that patients who survive have mutant but not absent enzymes, and the second that the abnormal enzyme has a much higher K i.e., a lower affinity, for the substrate of that enzyme, the maximum rate of reaction not being excessively reduced. Under these conditions, the substrate will accumulate, but when equilibrium is established at a higher concentration of substrate, a reaction rate can be measured, reflected as continued urea production. Substrate accumulation from this point of view is an adaptation to the abnormal enzyme. 

The adaption of man to chemical assault is quite extraordinary. It is intriguing that we are not more vulnerable than we are to the continued confrontation with new chemicals which challenge our microsomal enzymes. We have been preoccupied, rightly, with the strectural potential of drugs and metabolites to induce sensitization. Possibly a more productive approach would evolve from turning our attention to the host to analyze his means for preventing sensitization when assessment of in vitro characteristics of the drug indicate that sensitization should occur. 

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