Agouti Alleles Alter Cysteine and Glutathione Concentrations in Hair Follicles and Serum of Mice (Ay/a, AwJ/AwJ, and a/a)

Abstract

Ectopic overexpression of the agouti protein in the lethal yellow (Ay/a) mouse causes a yellow coat as well as the lethal yellow syndrome. Presence of thiols like glutathione (GSH) or cysteine (Cys) may regulate the conversion of dopaquinone to phaeomelanin in hair follicle melanocytes. GSH also plays important roles in cellular health and maintenance. Cys and GSH were measured using high-performance liquid chromatography in hair follicles and serum of AwJ/AwJ (agouti), Ay/a (yellow), and a/a (black) mice over a 20-d hair growth regeneration period. Agouti alleles modulate thiol concentrations. Ay/a hair follicles exhibited higher total thiol levels and an increased ratio of Cys to GSH. AwJ/AwJ mice showed intermediate levels, while a/a mice had lowest total thiol concentrations and a decreased ratio of Cys to GSH. Hair follicle cysteine concentrations showed yellow > agouti > black (p < 0.01). In all genotypes, unplucked skin and day O hair follicles showed GSH as the major thiol, but a shift to predominantly Cys on peak melanogenic days was seen. Presence of high concentrations of free cysteine support the hypothesis of phaeomelanin synthesis via cysteinyldopas. The Ay/a mouse had the most dramatic follicular thiol changes as well as a depression in serum thiols. An altered thiol metabolism in these and other Ay/a tissues might impair normal cell functioning to contribute to the lethal yellow syndrome.