4-Fluoro-DL-phenylalanine

After sheep were defleeced with mimosine, cyclophosphamide or N-[5-(4-aminophenoxy)pentyl]-phthalimide, the first samples of the new growth of wool differed markedly in composition from the pretreatment samples, there being substantial reductions in the high-tyrosine proteins and increases in the high-sulfur proteins. Similar results were obtained with mice dehaired with mimosine and with sheep treated with low levels of mimosine which resulted in weakened wool rather than depilation. The composition of later samples of the regrowth wool showed progressive changes with time. The high-tyrosine proteins tended to approach the pretreatment levels, although this may take up to 12 weeks to occur, whereas the levels of high-sulfur proteins, after the initial increase, often fell below normal. In experiments involving defleecing with cyclophosphamide, the level of the latter proteins was still below normal after 3 months. The possibility that this altered protein composition of keratin fibres is characteristic of that portion of fibre first produced by a new or regenerating follicle was investigated in sheep and mice. It was found that wool follicles regenerating after plucking, and newly operating follicles in young sheep and mice, also produced wool and hair with a reduced content of high-tyrosine proteins. It is suggested, therefore, that the apparent long-term inhibition of the high-tyrosine proteins may not be the direct consequence of the administration of the chemical but rather be characteristic of normal wool and hair regrowth. Infusion of an amino acid mixture lacking methionine into the abomasum of sheep caused the growth of weak wool but did not suppress the synthesis of the high-tyrosine proteins. This is in contrast with previous findings that treatments which weaken wool also suppress high-tyrosine proteins.

Varying amounts of DL-, L- or D-ethionine were administered intravenously to sheep, either as a continuous infusion, usually over 2 days, or as a single injection. Groups of sucking mice and rats, in their first cycle of hair growth, were given subcutaneous injections of DL-ethionine at several dose rates. Ethionine was a potent inhibitor of wool growth in sheep; the L- and D-isomers appeared equally effective. An infusion of 20 mg/kg DL-ethionine (c. 50 mg/kg0.75) given at a daily rate of 10 mg/kg for 2 days, or an injection of 40 mg/kg DL-ethionine (c. 100 mg/kg0.75), were sufficient to cause the growth of very weak wool and allow the fleece to be readily removed by hand within 3 weeks after dosing. The inhibition of wool growth was usually associated with a concentration of ethionine in blood plasma, during intravenous infusion, of 10 mumol/l or higher. An infusion of DL-ethionine at a daily rate of 1 mg/kg for 12 days caused the growth of weak fibres and substantially reduced both length growth rate and diameter of fibres. The toxicity of ethionine to sheep was dependent on the total dose and the duration of administration. An infusion of 40 mg/kg (20 mg/kg daily for 2 days) produced severe effects, but the sheep recovered; a dose of 14 mg/kg (2 mg/kg daily for 7 days) was lethal. The effects of ethionine on wool growth were reduced or prevented by the concurrent infusion of methionine (10-15 mol/mol ethionine). Doses of DL-ethionine as high as 460 mg/kg0.75 failed to cause hair loss in sucking mice. While body growth was severely retarded at this dose, no deaths occurred. Likewise, DL-ethionine failed to cause hair loss in sucking rats, but was lethal to some rats at a dose of 360 mg/kg0.75.

Sheep were given intravenous infusions of ethionine together with cycloleucine or reduced glutathione, in attempts to prevent the inhibition of wool growth by ethionine. Other sheep were given cycloleucine alone to measure effects on wool growth. Twenty-two compounds related to cystine, methionine, ethionine, lysine, phenylalanine and tyrosine were given as intravenous infusions to sheep to investigate their potential as depilatory agents. Nineteen of these compounds were also tested in mice during their first cycle of hair growth. The concurrent administration of cycloleucine with ethionine prevented the weakening of wool fibres caused by ethionine, but reduced glutathione was ineffective. Cycloleucine weakened wool fibres, as judged subjectively, and caused a small reduction in fibre diameter. Selenocystine and selenomethionine caused some hair loss in mice but selenocystine was also toxic. Both seleno-amino acids were toxic for sheep; selenocystine was lethal at 0.025 mmol kg-0.75 and selenomethionine at 0.09 mmol kg-0.75. Doses that permitted survival of sheep did not have depilatory effects. However, the presence of autophagic vacuoles in the cytoplasm of follicle bulb cells of sheep indicated that a toxic dose of selenocystine had potential depilatory activity. Other compounds investigated did not induce loss of wool or hair. Some compounds, notably 3-methylthiopropionic acid and S-(2-aminoethyl)-L-cysteine, were toxic to mice but not sheep. The methionine analogue, methoxinine (O-methyl-DL-homoserine), caused a substantial reduction in the strength of wool fibres and a prolonged alteration of the crimp pattern. It is suggested tentatively that cycloleucine inhibits methionine adenosyltransferase and thereby reduces or prevents the formation of S-adenosylethionine. The failure of various compounds related to methionine and ethionine to have any depilatory activity in sheep supports the view that ethionine influences wool growth via the formation of S-adenosylethionine.