Incorporation of Thiouracil and some Related Compounds into Growing Melanin

Abstract

Several drugs, mainly polycyclic amines, are accumulated in melanin‐containing tissues. They are bound to preformed melanin (both in vivo and in vitro). Thiouracil is accumulated into melanin according to another principle: It is incorporated as a false precursor during melanin formation. It is thus taken up only in growing melanin, e.g. in the eye of pigmented mouse foetuses or in melanomas. The acceptance of a foreign substance during the formation of a foetal tissue seems theoretically important. We are also interested in the practical viewpoint of using false melanin precursors as selective melanoma seekers. Some related substances are therefore compared with respect to incorporation into growing melanin. The thiouracil uptake in the ocular melanin of a 5 day old mouse was 276 times higher than that of a 3 month old mouse based on weight units of melanin. Thiourea is incorporated in growing melanin as well but also binds slightly to preformed melanin. Uracil and fluorouracil showed no specific uptake into growing melanin. It thus seems as if the sulfur is essential for the incorporation into the melanin polymer. 35S‐thiouracil and 2‐thio(2‐14C)uracil showed the same high uptake, indicating that at least part of the uracil moiety is incorporated together with the sulfur. There seems to be a relation between the property to be incorporated into melanin and the thyrostatic activity. Both in the formation of melanin and thyroid hormones, tyrosine is the physiological precursor and both reactions are catalyzed by oxidizing enzymes. Properly labelled thiouracil derivatives seem to be promising melanoma seekers for diagnostic and radiotherapeutic purposes.

Thioamides as False Melanin Precursors: Studies in Murine Melanomas

“…Earlier it has been shown that 2-thiouracil is accumulated in melanotic melanomas, apparently as a false melanin precursor (Dencker et al 1979(Dencker et al , 1981. The present investigation shows that methimazole and 5-iodo-2-thiouracil are similarly incorporated into melanin.…”

“…The concentration within the tumour varies greatly, apparently reflecting differences in the rate of melanin synthesis at the time of injection. lation in melanin of foetuses and newborn mice as well as in melanomas (Dencker et al 1979(Dencker et al , 1981. This paper describes the distribution of another thioamide (methimazole) in melanomabearing mice, but also compares a number of structurally related compounds to determine what are probably the main structural requirements of a chemical for being accepted as a false melanin precursor.…”

“…Pieces were either scraped off from thick tapefastened, freeze-dried sections (see above) or were dissected out by autopsy immediately after the animals had been killed. The tissue pieces were dissolved in Soluene-350@ (Packard) with exception of the tumours and the eyes which were dissolved in Soluene-10W (Packard) (Dencker et a/. 1981) and bleached by the addition of 0.2 ml isopropanol and 0.2 mlof 3570 hydrogen peroxide and incubated at 40" for 30 min., whereafter 15 ml Instagel@ (Packard) was added.…”

“…We have recently reported that thiouracil ( fig. 1) is a most selective, false precursor of melanin in vivo (Dencker et al 1979(Dencker et al , 1981, and if properly labelled with a radio-isotope it could be used for the diagnosis and possibly therapy of malignant melanomas. We report here on the accumulation of another thioamide, methimazole, which shows high selectivity for melanin as well.…”

Human hair follicle pigmentary unit as a direct target for modulators of melanogenesis, as studied by [14C]‐2‐Thiouracil incorporation

“…Previous studies performed in skin organ cultures, in cultured melanocytes and in melanocytes–keratinocytes co‐cultures have used [ 14 C]‐2‐TU as a specific pigmentation marker of synthesis of nascent melanins (2–5). After injection in mice, high selective retention of 2‐[ 14 C]‐TU also has been shown in melanoma cells, eyes and hair follicles (6). Recently, assays performed on anagen human hairs using Fontana–Masson staining in vitro have demonstrated a possible stimulation of hair melanogenesis by T‐oligos (7), but such studies are scarce and well known potent modulators of pigmentation remain to be assessed using a quantitative method on whole hair follicles in vitro .…”