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In defence of a special role for the iodo substituents in thyroid hormones
J. theor. Biol. (1975) 52,255-257
In Defence of a Special Role for the Iodo Substituents in Thyroid Hormones Jorgensen, Murray & Block (1974) have shown that some halogen-free thyronines have thyromimetic activity, a fact which, according to the authors, rules out any hypothesis which ascribes a unique functional role to the halogen substituents. In my opinion this inference is not justified for the iodo substituentsof the inner ring (3,5 positions). Thus, while 3,5dimethyl-3’-isopropyl-thyronine (Fig. 1) is the most active halogen-free thyronine derivative (18% of that of
FIG. 1. 3,5-yl-3’
L-thyroxine) its activity is unimpressive when compared with that of 3,5diiodo-3’-isopropyl-thyronine. The latter is more active than 3,5,3’-triiodothyronine which in turn is about six times more active than L-thyroxine (Wool, Fang 8c Selenkow, 1965). Therefore the effect of replacing the 3,5diiodo substituents by methyl groups is to reduce the activity to less than3%.
As another example, the activity of 3,5dimethyl-3’-iodo-thyronine (5% of that of L-thyroxine) may be compared with that of 3,5,3’-triiodothyronine: here the activity has beenreduced to lessthan 1%. The 3,5diiodo series is thus about two orders of magnitude more active than the 3,5dimethyl series. The inner iodo substituents must therefore play an additional, special, role. This may be concerned with heavy atom perturbation, an effect by which the spin conservation rule breaks down (McClure, 1949; Kasha, 1952; McClure, Blake & Hanst, 1954; McGlynn, Reynolds, Daigree & Christodoyleas, 1962; McGlynn, Sunseri & Christodoyleas, 1962). This 255
256
G.
CILENTO
possibility was first mentioned by Szent-GySrgyi (1957) ; and then, independently, by this author (Cilento, 1961) when he found a striking correlation between the effect of 3,5-substituents upon the hormonal activity of thyronine, and upon the lifetime of the triplet state of naphthalene, that is, upon the spin forbidden triplet + singlet transition. We have proposed (Cilento, 1965; Cilento & Berenholc, 1965; Cilento, Sanioto, Zinner & Berenholc, 1968; Cilento, 1973) that the hormone (or the receptor-hormone complex) participates in spin-forbidden energy transfer processes (Fig. 2) and have outlined a model for this transfer. The
FIG. 2. Spin-forbidden hormone komplex).
energy transfer processes involving the hormone (or the receptor-
growing evidence that non-emissive excited electronic states may be generated in biological processes (Cilento, 1973; Cilento, Nakano, Fukuyama, Suwa & Kamiya, 1974; White, Miano, Watkins & Breaux, 1974; Faria Oliveira, Sanioto & Cilento, 1974) lends considerable support to our proposal. The hypothesis of heavy atom perturbation is in no way ruled out by the activity of halogen-free thyronines, as claimed by Jorgensen, Murray 8z Block (1974). Indeed, heavy substituents are not necessary for promoting a spin-forbidden process such as the conversion of triplet energy into singlet energy: they only do so more efficiently (see Belyakov & Vassil’ev, 1970; Wilson & Schaap, 1971; and especially, Turro et al., 1974). Departmentof Biochemistry,Instituto de Quimica, Universidadede Sdo Patdo, C.P. 20780,Silo Paulo, Brazil
G.
CILENM
(Received21 August 1974)
REFERENCES V. A. & VASSU’EV, R. F. (1970). Photo&m. Photobiol.11,179.
Papers,
CILENID,G. (1%5).Photo&em.Photobiol.4,1243. CJLENTG,
G. (1973).
Q. Rev. Biophys.
6,485.
CILENTO, G. & BKWNI-IOLC, M. (1965). Biochim.biophys.Acta 94, 271. CILENKI,G., NAKANO,M., FUKUYAMA,H., SUWA, K. & KAMIYA, I. (1974). Biochem. biophys.Res.Commun. 58,2%. W, G., SANWKI,D. L., ZINNBR, K. & BERENHOLC,M. (1968). Photo&m. Photobiol.
7, 557. FAluA OLlvmA,
0. M. M.. Res.Gnnmun.s& 391.
SANIGTO,
D. L. & CILBNTO, G. (1974). Biochem.biophys.
LETTERS
TO
THE
EDITOR
257
JOROHNSEN,E. C., MURRAY, W. J. & BLOCK, P. (1974). J. med. Chem. 17,434. KASHA, M. (1952). J. them. Phys. 20,71. M~CL~RB, D. S. (1949). J. chetn. Phys. 17,905. MCCLURE, D. S., BLAKE, N. & HANST, P. L. (1954). J. them. Phys. 22,255. MCGL~NN, S. P., REYNOLDS, M. J., DAIGREE, G. W. & CHRISTOWYLEAS, N. D. (1962). J. phys. Chem. 66,2499. M&LYNN, S. P., Su~smu, R. & CHRISTODOYLEAS,N. (1962). J. them. Phys. 37, 1818. SZENT-GYGRG~I, A. (1957). Bioenergetics, pp. 24,27. New York: Academic Press. TURRO, N. J., LECHTKEN, P., SCHUSTER,G., ORELL, J., STEINMETZER, H.-C. & ADAM, W. (1974). J. Am. them. Sot. %, 1627. WHITE, E. H., MLQZO, J. D., WATKINS, C. J. & BREAIJX, E. J. (1974). Angew. Chem. 13,229. W-N, T. & SCHAAP, A. P. (1971). J. Am. them. Sot. 93,4126. WOOL, M., FANG, V. S. & SEL.ENKOW,H. A. (1965). Endocrinology 78,29.
In Defence of a Special Role for the Iodo Substituents in Thyroid Hormones Jorgensen, Murray & Block (1974) have shown that some halogen-free thyronines have thyromimetic activity, a fact which, according to the authors, rules out any hypothesis which ascribes a unique functional role to the halogen substituents. In my opinion this inference is not justified for the iodo substituentsof the inner ring (3,5 positions). Thus, while 3,5dimethyl-3’-isopropyl-thyronine (Fig. 1) is the most active halogen-free thyronine derivative (18% of that of
FIG. 1. 3,5-yl-3’
L-thyroxine) its activity is unimpressive when compared with that of 3,5diiodo-3’-isopropyl-thyronine. The latter is more active than 3,5,3’-triiodothyronine which in turn is about six times more active than L-thyroxine (Wool, Fang 8c Selenkow, 1965). Therefore the effect of replacing the 3,5diiodo substituents by methyl groups is to reduce the activity to less than3%.
As another example, the activity of 3,5dimethyl-3’-iodo-thyronine (5% of that of L-thyroxine) may be compared with that of 3,5,3’-triiodothyronine: here the activity has beenreduced to lessthan 1%. The 3,5diiodo series is thus about two orders of magnitude more active than the 3,5dimethyl series. The inner iodo substituents must therefore play an additional, special, role. This may be concerned with heavy atom perturbation, an effect by which the spin conservation rule breaks down (McClure, 1949; Kasha, 1952; McClure, Blake & Hanst, 1954; McGlynn, Reynolds, Daigree & Christodoyleas, 1962; McGlynn, Sunseri & Christodoyleas, 1962). This 255
256
G.
CILENTO
possibility was first mentioned by Szent-GySrgyi (1957) ; and then, independently, by this author (Cilento, 1961) when he found a striking correlation between the effect of 3,5-substituents upon the hormonal activity of thyronine, and upon the lifetime of the triplet state of naphthalene, that is, upon the spin forbidden triplet + singlet transition. We have proposed (Cilento, 1965; Cilento & Berenholc, 1965; Cilento, Sanioto, Zinner & Berenholc, 1968; Cilento, 1973) that the hormone (or the receptor-hormone complex) participates in spin-forbidden energy transfer processes (Fig. 2) and have outlined a model for this transfer. The
FIG. 2. Spin-forbidden hormone komplex).
energy transfer processes involving the hormone (or the receptor-
growing evidence that non-emissive excited electronic states may be generated in biological processes (Cilento, 1973; Cilento, Nakano, Fukuyama, Suwa & Kamiya, 1974; White, Miano, Watkins & Breaux, 1974; Faria Oliveira, Sanioto & Cilento, 1974) lends considerable support to our proposal. The hypothesis of heavy atom perturbation is in no way ruled out by the activity of halogen-free thyronines, as claimed by Jorgensen, Murray 8z Block (1974). Indeed, heavy substituents are not necessary for promoting a spin-forbidden process such as the conversion of triplet energy into singlet energy: they only do so more efficiently (see Belyakov & Vassil’ev, 1970; Wilson & Schaap, 1971; and especially, Turro et al., 1974). Departmentof Biochemistry,Instituto de Quimica, Universidadede Sdo Patdo, C.P. 20780,Silo Paulo, Brazil
G.
CILENM
(Received21 August 1974)
REFERENCES V. A. & VASSU’EV, R. F. (1970). Photo&m. Photobiol.11,179.
Papers,
CILENID,G. (1%5).Photo&em.Photobiol.4,1243. CJLENTG,
G. (1973).
Q. Rev. Biophys.
6,485.
CILENTO, G. & BKWNI-IOLC, M. (1965). Biochim.biophys.Acta 94, 271. CILENKI,G., NAKANO,M., FUKUYAMA,H., SUWA, K. & KAMIYA, I. (1974). Biochem. biophys.Res.Commun. 58,2%. W, G., SANWKI,D. L., ZINNBR, K. & BERENHOLC,M. (1968). Photo&m. Photobiol.
7, 557. FAluA OLlvmA,
0. M. M.. Res.Gnnmun.s& 391.
SANIGTO,
D. L. & CILBNTO, G. (1974). Biochem.biophys.
LETTERS
TO
THE
EDITOR
257
JOROHNSEN,E. C., MURRAY, W. J. & BLOCK, P. (1974). J. med. Chem. 17,434. KASHA, M. (1952). J. them. Phys. 20,71. M~CL~RB, D. S. (1949). J. chetn. Phys. 17,905. MCCLURE, D. S., BLAKE, N. & HANST, P. L. (1954). J. them. Phys. 22,255. MCGL~NN, S. P., REYNOLDS, M. J., DAIGREE, G. W. & CHRISTOWYLEAS, N. D. (1962). J. phys. Chem. 66,2499. M&LYNN, S. P., Su~smu, R. & CHRISTODOYLEAS,N. (1962). J. them. Phys. 37, 1818. SZENT-GYGRG~I, A. (1957). Bioenergetics, pp. 24,27. New York: Academic Press. TURRO, N. J., LECHTKEN, P., SCHUSTER,G., ORELL, J., STEINMETZER, H.-C. & ADAM, W. (1974). J. Am. them. Sot. %, 1627. WHITE, E. H., MLQZO, J. D., WATKINS, C. J. & BREAIJX, E. J. (1974). Angew. Chem. 13,229. W-N, T. & SCHAAP, A. P. (1971). J. Am. them. Sot. 93,4126. WOOL, M., FANG, V. S. & SEL.ENKOW,H. A. (1965). Endocrinology 78,29.