546 2. ANALOGS OF ENZYME REACTION COMPONENTS 



primary effects by interference with flavoenzymes, and has come to be the 

 most widely used substance to detect the participation of a flavin com- 

 ponent in an enzyme or metabolic system. Quinacrine not only inhibits the 



CH,CH,CH3-N^^'^' 



CH,0 



Quinacrine 



malarial organism but, in common with other acridines, suppresses the 

 growth of various bacteria. For example, Lactobacillus casei is inhibited 

 and this seems to be related to flavin metabolism since the maximal con- 

 centration at which growth occurs is 0.12 niM when riboflavin is 0.00066 mM 

 and 0.49 mM when riboflavin is 10 times the previous concentration (Ma- 

 dinaveitia, 1946). Spore germination of B. subtilis (Falcone et at., 1959) and 

 B. coagvlans (Amaha and Nakahara, 1959) induced by L-alanine is inhibited 

 58% by 0.1 mM quinacrine and nearly completely by 1 mM. 



The toxic efl^ects observed in experimental animals and man — for ex- 

 ample, gastrointestinal (abdominal pain, diarrhea, nausea), dermatological 

 (eczematoid dermatitis, lichen planus), central nervous system (psychoses), 

 and others — do not appear to be related to riboflavin deficiency, and the 

 typical syndrome of deficiency has never been produced by quinacrine. 

 Thus one must assume that other actions are probably of more importance 

 in animals. One characteristic of quinacrine is its remarkable ability to be 

 accumulated in the tissues during chronic administration, and eventually 

 the tissue levels are hundreds or thousands of time higher than in the serum 

 (see Table 1-8-1). This is evident from the yellow coloration of the tissues. 

 These levels, of course, do not represent free quinacrine and the accumula- 

 tion is due to the high affinity of various tissue components for quinacrine. 

 It is bound in the cytoplasm, the mitochondria, and the nucleus; equilibra- 

 tion of isolated nuclei with quinacrine results in a 200-fold concentration 

 differential (Reiner and Gellhorn, 1956). Proteins, nucleic acids, and nu- 

 cleoproteins bind quinacrine strongly, and some of the inhibitory, muta- 

 genic, and carcinostatic effects have been attributed to such binding. It 

 is thus clear that quinacrine can be bound at many loci in the cell. 



Effects of Quinacrine on Enzymes 



Many enzymes are inhibited by quinacrine (Table 2-34). In some cases 

 the inhibition is competitive (or at least reduced by increasing the concen- 

 tration of FMN or FAD) and in others it is not. Quinacrine has come to 



