Ovulation-Inducing Activity of Luliberin (LHRH) Complexed by Copper( II), Nickel( II), and Zinc( II) Ions Henryk Kozhwski, Elibieta Masiukiewicz, Elibieta Potargowicz, Barbara Rzeszotarska, and Anna Walczewska-Sumorok HK. Institute of Chemistry, University of Wroclaw, Wroclaw, Poland.-EM, BR. stitute of Chemistry, Pedagogical University of Opole, Opole, Poland.-EEP, AW-S. stitute of Physiology and Biochemistry, School of Medicine, Ldd?, Poland
ZnIn-
ABSTRACT We have shown that the complexation of luteinizing hormone releasing hormone, luliberin (LHRH), a hypothalamic neurohormone, by Cu(II), Ni(II), and Zn(II) may affect its basic, ovulation-inducing potency in the dose responsive manner. Some explanation of the obtained results are offered here.
INTRODUCTION Luliberin
(LHRH,
gonadoliberin,
GnRH) is a decapeptide
amide, of the sequence:
Glp-His-Tip-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH*. The best known action of this neurohormone is the induction of luteinizing hormone (LH) and follicle stimulating hormone (FSH) release from the anterior pituitary and thereby the evoking of the ovulation [ 11. The involvement of metal ions in the biochemistry of LH-RH seems to be very likely and various as well. Already Tsou et al. [2] have observed the increase of LHRH levels in the pituitary stalk of the rabbit after systematic administration of cupric acetate. The series of current works of Barnea et al. [3-171 has revealed a rich variety of the effects caused by metal ions, especially by CuHis complex [I61 on biological behavior of gonadoliberin. This group reported among the others that copper, particularly partly coordinated cupric ions in the complex with histidine or cysteine stimulates the release of LH-RH from isolated hypothalamic granules
Address reprint requests to Professor H. Kozlowski, Joliot-Curie, 14, 50-383, Wroclaw, Poland.
Institute of Chemistry,
University
of Wroclaw,
F.
121 40, 121-125 (1990) @ 1990 Elsevier Science Publishing Co., Inc., 655 Avenue of the Americas, NY, NY ICNIIO 0162-0134/90/$3.50
Journalof InorganicBiochemistry,
)
l
122
H. Koztowski
et ai
and median eminence explants. Copper released in the vicinity of i,H-RH neurons interacts with specific sites on this peptide axonal terminals. which causes the release of neuropeptide. Also Ni(Il) complex. NiHis, stimulates the hormone release although to a lesser extent. The exact mechanism of‘ the hnrnhonc r~lcabe prot*c.ss b> the metal complexes is not yet known. It stems. however, to be likely that metal ions or their histidine complexes ma! interact with the rsleased hormone formln~ binary or ternark complex species. The mstal ion complexes with LA-RH were shown to bc very stable in the neutral pH range j 18. 191 and thus the complex formation in natural systcrns is very lihcly. The interaction of Zn( II) ions with this peptidc ix much ~cakcr ihan that ot Cu( II; of Ni(Ilj ions but it is ctfcc‘tivc enough to influence pcbtentialiy the neuropeptidc acrivib 1191. The chemical and biological studies on thy mctai complzxcs u,ith the other ncurohormone, thyroliberin TRF. have indicated that metal ions may influence the biological activity of a peptide hormone ]20-.23]. It EScvitlcnt. ti\pccEally for pcptidrs which arc effective ligands, i.e.. those containing His residue in their sequen~c. The potential importance of copper ions in the biochemrr:r> of hr:iin peptides may also bc indicated by the fact that the concentration of tius metal ~ri [he hypc.,thalamic axonal rerminals is 1 -2 orders of magnituclc greater than, s:.;: , :n phsmr /24--.2!5]~ There arc: no reports :lvailablc about thr metal ion l”fitY‘l Oil the i?asrc c,:%latic)rlinducing activity of I-H-RH. Hence.WC have undertaken rhc invesrigations on the influence of metal ion i i‘uc II). Ni(IIj. and Zniil)) contplcxes 1%Ith gonadolihcrin on the ovulation protest in r:,ta and the reaulrs are pre~.entcJ in thih pq~~r.
EXPERIMENTAL Synthesis
of the Complexes
of LH-RH
with Metal Ions
Metai complexes were prepared according to the proccdurc described earlier tOl the respective compounds with TRF [20]. Cu(II)-LH-RH was obtained by fusion oi the ethanol solutions
ZnIn-
ABSTRACT We have shown that the complexation of luteinizing hormone releasing hormone, luliberin (LHRH), a hypothalamic neurohormone, by Cu(II), Ni(II), and Zn(II) may affect its basic, ovulation-inducing potency in the dose responsive manner. Some explanation of the obtained results are offered here.
INTRODUCTION Luliberin
(LHRH,
gonadoliberin,
GnRH) is a decapeptide
amide, of the sequence:
Glp-His-Tip-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH*. The best known action of this neurohormone is the induction of luteinizing hormone (LH) and follicle stimulating hormone (FSH) release from the anterior pituitary and thereby the evoking of the ovulation [ 11. The involvement of metal ions in the biochemistry of LH-RH seems to be very likely and various as well. Already Tsou et al. [2] have observed the increase of LHRH levels in the pituitary stalk of the rabbit after systematic administration of cupric acetate. The series of current works of Barnea et al. [3-171 has revealed a rich variety of the effects caused by metal ions, especially by CuHis complex [I61 on biological behavior of gonadoliberin. This group reported among the others that copper, particularly partly coordinated cupric ions in the complex with histidine or cysteine stimulates the release of LH-RH from isolated hypothalamic granules
Address reprint requests to Professor H. Kozlowski, Joliot-Curie, 14, 50-383, Wroclaw, Poland.
Institute of Chemistry,
University
of Wroclaw,
F.
121 40, 121-125 (1990) @ 1990 Elsevier Science Publishing Co., Inc., 655 Avenue of the Americas, NY, NY ICNIIO 0162-0134/90/$3.50
Journalof InorganicBiochemistry,
)
l
122
H. Koztowski
et ai
and median eminence explants. Copper released in the vicinity of i,H-RH neurons interacts with specific sites on this peptide axonal terminals. which causes the release of neuropeptide. Also Ni(Il) complex. NiHis, stimulates the hormone release although to a lesser extent. The exact mechanism of‘ the hnrnhonc r~lcabe prot*c.ss b> the metal complexes is not yet known. It stems. however, to be likely that metal ions or their histidine complexes ma! interact with the rsleased hormone formln~ binary or ternark complex species. The mstal ion complexes with LA-RH were shown to bc very stable in the neutral pH range j 18. 191 and thus the complex formation in natural systcrns is very lihcly. The interaction of Zn( II) ions with this peptidc ix much ~cakcr ihan that ot Cu( II; of Ni(Ilj ions but it is ctfcc‘tivc enough to influence pcbtentialiy the neuropeptidc acrivib 1191. The chemical and biological studies on thy mctai complzxcs u,ith the other ncurohormone, thyroliberin TRF. have indicated that metal ions may influence the biological activity of a peptide hormone ]20-.23]. It EScvitlcnt. ti\pccEally for pcptidrs which arc effective ligands, i.e.. those containing His residue in their sequen~c. The potential importance of copper ions in the biochemrr:r> of hr:iin peptides may also bc indicated by the fact that the concentration of tius metal ~ri [he hypc.,thalamic axonal rerminals is 1 -2 orders of magnituclc greater than, s:.;: , :n phsmr /24--.2!5]~ There arc: no reports :lvailablc about thr metal ion l”fitY‘l Oil the i?asrc c,:%latic)rlinducing activity of I-H-RH. Hence.WC have undertaken rhc invesrigations on the influence of metal ion i i‘uc II). Ni(IIj. and Zniil)) contplcxes 1%Ith gonadolihcrin on the ovulation protest in r:,ta and the reaulrs are pre~.entcJ in thih pq~~r.
EXPERIMENTAL Synthesis
of the Complexes
of LH-RH
with Metal Ions
Metai complexes were prepared according to the proccdurc described earlier tOl the respective compounds with TRF [20]. Cu(II)-LH-RH was obtained by fusion oi the ethanol solutions
