THE

TRICHOGENIC ACTION GROUP IN HEREDITARY OF THE

BY

OF THE SULFHYDRYL HYPOTRICHOSIS RAT

AND

GUSTAV of Hygiene

J. MARTIN and Public University, for

R.

E.

GARDNER
of Immuwloqy,

(Fmn

the
School

BiochenaicalLaboratory

and the Deparlment Health, the Johns Baltimore) Juuc II, 1935)

Hopkins

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(Received

publication,

The contribution of Hammett. (1) to the function of glutat,hione in development and groJvth, combined with the work of Itter, Orent,, and McCollum (2) in demonst,rat,ing glutathione as a complicating factor in vitamin Bz deficiency, has led to renew-cd interest The lnt,tcr group demonstrated a cure of in sulfur metabolism. alopecia in rats by the addition of ghltabhione or cysteine to a vitamin Bz-deficient diet. One of us has observed (unpublished data) that the regression of a transplantable sarcoma stimulnt~cs the growth of hair cithcr diffuse or localized in young hairless rats. Kcnnaway and Hiegcr (3) reported that tumor tissue contains gluta.thionc, which led us t,o suspect that the oral administration of this compound might stimulate the growth of hair in the hypotrichotic rat. Since Bierich and Kalle (4) state that tumors do not contain free cysteine, we anticipated no effect from cyst&e.
EXPERIMENTAL

The Test Animal-Reports of the inheritance of hypotrichosis or hairlessness in the strain of rats used as test animals in these experiments were made by Roberts (5) in 1924 and 1926. The hypotrichosis was found to bc due to a single rccessire factor. The strain originated from :t wild male rat (Mus norvegicus) devoid of hair according to Roberts, who very kindly supplied our laboratory with a pair of these animals in 1927, which lint has been continued since that time. Our findings on Mendelian
193

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Hereditary

Hypotrichosis

ratio shown by this charact,er are in agreement with those of Roberts. Emery (6) has studied the estrual cycle and the weights of organs in relation to the hypophysis in this hairless strain of rat.s. Spleen, pit,uitary, thyroids, and testes are similar in albino, heterozygous, and hairless males. The kidneys and adrenals were large1 in heterozygous and hairless rats of both sexes. The estrual Irregucycles were prolonged in diestrus in the hairless animal. larities were common and often complete absence of estrual cycle was noted. Emery reports an increased amount of gonad.stimu-

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FIG. 1. Hereditary hypotrichosis in the rat. The lower cystine-fed litter mate of the rat in upper view, receiving mented ration.

view shows a the unsupple-

lating hormone in the hypophysis of the hairless males and females as compared to albinos. The objective of this work was to determine the effect of the administration of various sulfur-containing compounds to the test animal, the hairless rat. The animals were maintained on the McCollum stock diet and given supplements in the form of crystalline cysteine, cystine, and glutathione. The dosages were made comparable by feeding the various compounds at a level which would furnish equal amounts of cysteine provided the molecule was completely broken don-n to
1 Wheat, maize, rolled oats, flaxseed oil meal, casein, whole milk powder, calcium carbonate, sodium chloride, iron citrate, and copper su1fat.e.

G. J. Martin

and R. E. Gardner

195

free cysteine. The dosages were cysteine 5 mg., cystine 5 mg., and glutathione 15 mg. A total of twenty hairless rats was used experimentally. The rats were given these supplements when 35 to 40 days of age, at which time they were almost completely hairless. The entire hairless colony of some 70 males and females formed the controls over this series. Not one rat among these ever showed continued indications of recovering the hairy coat. Results Glutathione-When fed at 15 mg. per day per rat, over a period of 45 days, this substance failed to induce the slightest indication of response in the test animal. Cystine-When fed at a 5 mg. level per day per rat, cystine stimulated the growth of a hairy coat within 1 month, as indicated in Fig. 1. The coat was maintained for a period of 2 weeks and was subsequently lost entirely. Higher dosage (30 mg.) failed to initiate a regrowth of hair over a period of 30 days. Cysteine-When fed at 5 mg. per day per rat, cysteine stimulated the growth of a complete coat of hair within 2 weeks. The animals maintained the coat over a period of 1 month, at which time the experiment was discontinued.
DISCUSSION

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The results obtained are interpreted to indicate the hereditary absence in the hairless rat of an enzyme capable of breaking glutathione or other peptide linkages involving sulfur-containing groups into the constituent amino acids. Were this not true, one would expect glutathione to replace cystine in stimulating the resumption of the growth of a coat of hair. The fact that cystine will not maintain the hair might be interpreted by assuming that the effect observed was due to a small amount of contaminating cysteine in the cystine fed, but was not in amounts sufficient to maintain the coat in the larger animal; and, in addition to this, the possible absence in the hairless rat of an enzyme splitting the dithiol grouping. The report of Itter, Orent, and McCollum (2), demonstrating the cure of alopecia in the vitamin Bz-deficient rat by the daily feeding of glutathione or cysteine, can be interpreted in the light

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Hereditary

Hypotrichosis

of this work. They report a lesser effect to be produced by the cysteine. Considering these results with those obtained with the hairless rat, one is led to conclude that in the case of the vitamin Bz-deficient rats the glutathione was broken down and acted by way of the liberated cysteine. The mechanism for the hydrolysis of the tripeptide, glutathione, is hereditarily absent in the hairless rat, and consequently, glutathione will not bring about the same effect as regards the stimulation of the growth of hair in the hairless rat. The importance from the standpoint of genetics of the observation of the growth of hair in animals that are hereditarily free of hair cannot be overlooked. Hereditary anomalies of metabolism are rare. These inborn errors of metabolism present from birth include albinism, pentosuria, alkaptonuria, cystinuria, congenital porphyruria, and congenital steatorrhea. To these we may now add the condition of hypotrichosis in the rat. The relation of this condition in the rat to alopecia totalis in the human is a subject for further study. The possibility that these hairless animals were cystinuric was tested chemically and by microscopic examination of urine for crystals of cystine. The results were entirely negative.
CONCLUSION

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Cysteine through the sulfhydryl group acts as a stimulant to the hair follicle, bringing about a trichogenic action in heredit,ary hypotrichosis of the rat. The authors wish to express their appreciation for the interest shown by Dr. E. V. McCollum and Dr. R. R. Hyde.
BIBLIOGRAPHY

F. S., Science, 79, 457 (1934). 2. Itter, S., Orent, E. R., and McCollum, E. V., J. Biol. Chem., (1935). 3. Kennaway, E. L., and Hieger, I., Biochem. J., 21, 751 (1927). 4. Bierich, R., and Kalle, K., 2. physiol. Chem., 176, 292 (1928). 5. Roberts, E., Anat. Rec., 29, 141 (1924-25); 34, 172 (1926-27). 111, 392 (1935). 6. Emery, F. E., Am. J. Physiol.,

1. Hammett,

108, 585