DISTRIBUTION AND METABOLISM 583 



of sulfate conjugates in the urine (Ellinger, 1923; Speranskaya-Stepanova, 

 1940), whereas 3,5-dimethoxytoluquinone is conjugated mainly with glu- 

 curonate in the rabbit (Glock et al, 1945). Toluquinone is conjugated 

 primarily with amino acids. What fraction of the benzoquinones is me- 

 tabolized more drastically, e. g., by substitution of new groups on the ring 

 or cleavage of the ring, is not known, although fungi can degrade p-benzo- 

 hydroquinone to keto acids (Friedrich, 1956). The naphthoquinones ap- 

 pear to be reasonably stable in the body, as far as we know, since most of 

 that administered appears eventually in the urine, but only menadione has 

 been extensively studied. With respect to conjugation, the naphthoquinones 

 do not differ markedly from the benzoquinones, the urinary products 

 being sulfate esters and glucuronides (Richert, 1951; Jacques et al., 1954; 

 Marrian and Maxwell, 1956; Bray and Garrett, 1961), although there is 

 evidence for a phosphate also in the chromatographic separation used by 

 Jacques. It may be noted that there is nothing from the excretory data 

 to support reactions of the quinones with thiols, although quite possibly 

 they have simply not been detected. Exactly what happens to the quinones 

 which do react with the thiols in the blood and tissues is not known, and 

 there is no doubt that such reactions occur (Canady and Roe, 1956). 



The fate and metabolism of the phosphorylated quinols are especially 

 important in understanding how they exert their antimitotic effects. Ad- 

 ministration of menadiol-diP^- to rats and tracing of it and P^^- in the 

 tissues led Neukomm et al. (1953) to conclude that menadiol-diP penetrates 

 into cells — that the phosphate groups indeed facilitate the penetration — 

 and that some of the menadiol-diP is fixed and the rest is dephosphorylated. 

 There may even be some exchange between menadiol-diP^^ and P,^'-. It 

 was also thought that tissues with the most rapid division rate incorporate 

 the menadiol-diP most readily. Morrison and Crowley (1952) also used 

 menadiol-diP^- but concluded that the phosphate groups are rapidly split 

 off and the radioactivity is distributed as P^^^ Menadiol-diP is dephospho- 

 rylated in human plasma by alkaline phosphatase but at physiological 

 pH the rate is fairly slow, so that it can be transferred throughout the body 

 without much hydrolysis (Ramasarma et al., 1959). Marrian and Maxwell 

 (1956) preferred to use menadiol-diP-2-C^^H3 because of the stability of 

 the isotopic position, and 90 min after administration to rats could recover 

 around 70% of the activity (33% in the urine, 5.5% free in the blood and 

 tissues, 1% in the respiratory CO2, and 31% fixed in some form in the 

 tissues). There is no particular pattern of uptake by the tissues of tumor- 

 bearing rats, only the kidney showing a significantly more elevated level, 

 and the concentrations are uniformly low, with differential absorption ratios 

 in the range 0.1-0.4 for most tissues. Thus very little is metabolized to 

 release the 2-methyl group as C^^Oa, but what happens to the 25-30% 

 which is unaccounted for ? These results do not bear directly on the problem 



