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Fig. 4. The melanocytotoxicity of MoTP is mediated by tyrosinase activity.
(A) The chemical structure of (2-morpholinobutyl)-4-thiophenol (MoTP).
(B) Dendritic (healthy) melanocytes (black arrowheads) in an untreated
larva at 3 dpf. (C) When larvae were incubated in MoTP solution from 14
to 72 hpf, no neural crest-derived melanocytes were observed, but RPE is
lightly pigmented (black arrow). (D,E) When 48 hpf larvae with
pigmented melanocytes were shifted to MoTP, within 24 hours, larval
melanocytes had become punctate (white arrowheads in D) and began to extrude
from the epidermis (white arrow in E), a hallmark of melanocyte cell death.
(F) The melanocytotoxicity of MoTP was blocked by PTU, as indicated by
the dendritic appearance of lightly pigmented melanocytes (black arrowheads in
F) following co-incubation of MoTP and PTU from 48 to 72 hpf. (G) The
chemical structure of 4-hydroxyanisole (4-HA). (H) When larvae were
incubated with 4-HA from 14 to 72 hpf, the same punctate melanocyte pattern of
cell death appeared (white arrowheads). (I) Illustration of the
mechanism of 4-HA melanocytotoxicity (see
Riley, 1985). Note that
tyrosinase converts the prodrug 4-HA to a cytotoxic o-quinone. Because copper
is an essential cofactor for tyrosinase, its activity is blocked by
co-incubation with PTU, a copper chelator. Timelines (gray) below the panels
indicate the period of drug treatments (red) and analysis time (vertical line
above timelines). Scale bars: in H, 500 µm for B-D,F,H; in E, 50 µm.
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