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Luteal Progesterone Biosynthesis in Cattle and its Molecular Control Mechanism

Year 2019, Volume: 10 Issue: 3, 125 - 134, 30.12.2019

Ruhi Kabakçı Ayşe Arzu Yiğit

Abstract



The corpus luteum (CL) takes an important place in
cows which are able to reproductive activity throughout the year with a regular
estrus cycle lasting twenty-one days. Corpus luteum occurs at the site of
follicle wreck immediately after ovulation and maintains its presence during
diestrus phase which is the longest period of the estrous cycle. The most
critical and essential function of the CL is the production of progesterone (P4). This
function is performed by the small and large luteal cells which are
differentiated from theca and granulosa cells in the follicle wall by
stimulation of luteinizing hormone (LH). Progesterone synthesized from
cholesterol via steroidogenic enzymes has important roles such as regulation of
estrus cycle and maintenance of pregnancy. In this review, it is presented the
molecular control mechanism of progesterone biosynthesis in bovine luteal cells
and the steroidogenic enzymes such as cytochrome p450s (CYP11A1), steroidogenic
acute regulatory (StAR) protein, 3-Hydroxysteroid dehydrogenase (3β-HSD). It is
thought that reproductive physiology will be better understood by knowing the details of molecular
mechanisms of cows which have a significant economic value and should have a
healthy reproductive system.

Keywords

Cow Progesterone Synthesis Cytochrome p450s StAR Reproduction 3β-HSD

References

  • Alaçam, E. (2010). Evcil hayvanlarda doğum ve infertilite, 7th (ed.), Ankara, Turkey: Medisan.
  • Alila, H., Dowd, J., Corradino, R., Harris, W., ve Hansel, W. (1988). Control of progesterone production in small and large bovine luteal cells separated by flow cytometry. Journal of Reproduction and Fertility, 82(2), 645-655.
  • Alila, HW., ve Dowd, JP. (1991). The control of corpus luteum function in domestic ruminants. Oxford Reviews of Reproductive Biology, 13, 203-237.
  • Azhar, S., ve Reaven, E. (2002). Scavenger receptor class bi and selective cholesteryl ester uptake: Partners in the regulation of steroidogenesis. Molecular and Cellular Endocrinology, 195(1), 1-26.
  • Ball, PJH., ve Peters, AR. (2007). Reproduction in cattle, 3rd ed. (ed.), Australia: Blacjwell Publishing.
  • Bao, B., ve Garverick, HA. (1998). Expression of steroidogenic enzyme and gonadotropin receptor genes in bovine follicles during ovarian follicular waves: A review. Journal of Animal Science, 76(7), 1903-1921.
  • Brown, MS., ve Goldstein, JL. (1986). A receptor-mediated pathway for cholesterol homeostasis. Science, 232(4746), 34-47.
  • Cameron, JL., ve Stouffer, RL. (1982). Gonadotropin receptors of the primate corpus luteum. Ii. Changes in available luteinizing hormone-and chorionic gonadotropin-binding sites in macaque luteal membranes during the nonfertile menstrual cycle. Endocrinology, 110(6), 2068-2073.
  • Carr, BR., Macdonald, PC., ve Sımpson, ER. (1980). The regulation of de novo synthesis of cholesterol in the human fetal adrenal gland by low density lipoproteinand adrenocorticotropin. Endocrinology, 107(4), 1000-1006.
  • Chegini, N., Lei, Z., Rao, CV., ve Hansel, W. (1991). Cellular distribution and cycle phase dependency of gonadotropin and eicosanoid binding sites in bovine corpora lutea. Biology of Reproduction, 45(3), 506-513.
  • Davidson, AP., ve Stabenfeldt, GH. (2007). Reproduction and lactation, In Cunningham, JG., ve Klein, BG (Cunningham, JG., ve Klein, BG(Cunningham, JG., ve Klein, BGs.), Cunningham's textbook of veterinary physiology. 4th (ed.), St. Louis, MO: Saunders, an imprint of Elsevier Inc; pp. 465-474.
  • Davis, JS. (1991). Interactions among the camp and ip 3/dag intracellular signaling systems in bovine luteal cells, InSignaling mechanisms and gene expression in the ovary. Springer; pp. 39-53.
  • Goravanahally, MP., Sen, A., Inskeep, EK., ve Flores, JA. (2007). Pkcepsilon and an increase in intracellular calcium concentration are necessary for pgf2alpha to inhibit lh-stimulated progesterone secretion in cultured bovine steroidogenic luteal cells. Reproductive Biology and Endocrinology, 5(1), 37.
  • Graham, JD., ve Clarke, CL. (1997). Physiological action of progesterone in target tissues 1. Endocrine Reviews, 18(4), 502-519.
  • Grummer, R., ve Carroll, D. (1988). A review of lipoprotein cholesterol metabolism: Importance to ovarian function. Journal of Animal Science, 66(12), 3160-3173.
  • Hansel, W., Alila, HW., Dowd, JP., ve Yang, X. (1987). Control of steroidogenesis in small and large bovine luteal. Cells. Australian Journal of Biological Sciences, 40(3), 331-348.
  • Hartung, S., Rust, W., Balvers, M., ve Ivell, R. (1995). Molecular cloning and in vivo expression of the bovine steroidogenic acute regulatory protein. Biochemical and Biophysical Research Communications, 215(2), 646-653.
  • Hu, J., Zhang, Z., Shen, W-J., ve Azhar, S. (2010). Cellular cholesterol delivery, intracellular processing and utilization for biosynthesis of steroid hormones. Nutrition & metabolism, 7, 47-47.
  • Johnson, WJ., Phillips, MC., ve Rothblat, GH. (1997). Lipoproteins and cellular cholesterol homeostasis, In Bittman, R (Bittman, R),Bittman, Rs.), Cholesterol. Springer; pp. 235-276.
  • Krisans, SK. (1996). Cell compartmentalization of cholesterol biosynthesisa. Annals of the New York Academy of Sciences, 804(1), 142-164.
  • Milvae, R., ve Hansel, W. (1980). The effects of prostacyclin (pgi2) and 6-keto-pgf1α on bovine plasma progesterone and lh concentrations. Prostaglandins, 20(4), 641-647.
  • Milvae, R., ve Hansel, W. (1983). Prostacyclin, prostaglandin f2α and progesterone production by bovine luteal cells during the estrous cycle. Biology of Reproduction, 29(5), 1063-1068.
  • Miyamoto, A., Kshirasuna, T., Bollwein, H., ve Schams, D. (2011). Regulation of corpus luteum development and maintenance: Specific roles of angiogenesis and action of prostaglandin f2α. Reprod Domest Anim, 289.
  • Nishizuka, Y. (1984). Turnover of inositol phospholipids and signal transduction. Science, 225(4668), 1365-1370.
  • Nishizuka, Y. (1986). Studies and perspectives of protein kinase c. Science, 233(4761), 305-312.
  • Niswender, GD. (2002). Molecular control of luteal secretion of progesterone. Reproduction, 123(3), 333-339.
  • Niswender, GD., Juengel, JL., Silva, PJ., Rollyson, MK., ve Mcintush, EW. (2000). Mechanisms controlling the function and life span of the corpus luteum. Physiological Reviews, 80(1), 1-29.
  • Norman, AW., ve Litwack, G. (1997). Hormones, 3rd (ed.), USA: Academic Press.
  • Papadopoulos, V., Baraldi, M., Guilarte, TR., Knudsen, TB., Lacapère, J-J., Lindemann, P., Norenberg, MD., Nutt, D., Weizman, A., ve
  • Zhang, M-R. (2006). Translocator protein (18 kda): New nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. Trends in Pharmacological Sciences, 27(8), 402-409.
  • Papadopoulos, V., ve Brown, AS. (1995). Role of the peripheral-type benzodiazepine receptor and the polypeptide diazepam binding inhibitor in steroidogenesis. The Journal of steroid biochemistry and molecular biology, 53(1-6), 103-110.
  • Reece, WO., Erickson, HH., Goff, JP., ve Uemura, EE. (2015). Dukes' physiology of domestic animals, 13th (ed.), USA: Am Vet Med Assoc.
  • Rekawiecki, R., Kowalik, M., Slonina, D., ve Kotwica, J. (2008). Regulation of progesterone synthesis and action in bovine corpus luteum. Journal of Physiology and Pharmacology, 59(9), 75-89.
  • Richards, JS., Russell, DL., Ochsner, S., ve Espey, LL. (2002). Ovulation: New dimensions and new regulators of the inflammatory-like response. Annual Review of Physiology, 64(1), 69-92.
  • Romani, F., Tropea, A., Scarinci, E., Dello Russo, C., Lisi, L., Catino, S., Lanzone, A., ve Apa, R. (2013). Endocrine disruptors and human corpus luteum: In vitro effects of phenols on luteal cells function. Journal of Environmental Science and Health. Part C: Environmental Carcinogenesis & Ecotoxicology Reviews, 31(2), 170-180.
  • Rosenson, RS., Brewer Jr, HB., Davidson, WS., Fayad, ZA., Fuster, V., Goldstein, J., Hellerstein, M., Jiang, X-C., Phillips, MC., ve Rader, DJ. (2012). Cholesterol efflux and atheroprotection: Advancing the concept of reverse cholesterol transport. Circulation, 125(15), 1905-1919.
  • Schatten, H., ve Constantinescu, GM. (2007). Comparative reproductive biology, 1st: Wiley Online Library.
  • Seedorf, U., Ellinghaus, P., ve Nofer, JR. (2000). Sterol carrier protein-2. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids, 1486(1), 45-54.
  • Sewer, MB., ve Li, D. (2008). Regulation of steroid hormone biosynthesis by the cytoskeleton. Lipids, 43(12), 1109.
  • Shen, W-J., Patel, S., Natu, V., Hong, R., Wang, J., Azhar, S., ve Kraemer, FB. (2003). Interaction of hormone-sensitive lipase with steroidogeneic acute regulatory protein facilitation of cholesterol transfer in adrenal. Journal of Biological Chemistry, 278(44), 43870-43876.
  • Skarzynski, DJ., ve Okuda, K. (2010). Inter- and intra-cellular mechanisms of prostaglandin f2alpha action during corpus luteum regression in cattle. Society of Reproduction and Fertility Supplement, 67, 305-324.
  • Stancu C, SA. (2001). Statins: Mechanism of action and effects. Journal of Cellular and Molecular Medicine, 5(04), 378-387.
  • Stocco, C., Telleria, C., ve Gibori, G. (2007). The molecular control of corpus luteum formation, function, and regression. Endocrine Reviews, 28(1), 117-149.
  • Stone, D., ve Hechter, O. (1954). Studies on acth action in perfused bovine adrenals: The site of action of acth in corticosteroidogenesis. Archives of Biochemistry and Biophysics, 51(2), 457-469.
  • Tsang, PC. (2016.) Contrıbutıons of the ovary to fertılıty in daıry cows. slideplayer, Erişim adresi: [https://slideplayer.com/slide/10687536/], Erişim tarihi: 14.11.2019.
  • Wade, RL., Van Andel, RA., Rice, SG., Banka, CL., ve Dyer, CA. (2002). Hepatic lipase deficiency attenuates mouse ovarian progesterone production leading to decreased ovulation and reduced litter size. Biology of Reproduction, 66(4), 1076-1082.
  • Walsh, SW., Mehta, JP., Mcgettigan, PA., Browne, JA., Forde, N., Alibrahim, R., Mulligan, F., Loftus, B., Crowe, MA., ve Matthews, D. (2012). Effect of the metabolic environment at key stages of follicle development in cattle: Focus on steroid biosynthesis. Physiological Genomics, 44(9), 504-517.
  • Yılmaz, B. (1999). Hormonlar ve üreme fizyolojisi, 1st (ed.), Ankara: Feryal Matbaacılık.

İNEKLERDE LUTEAL PROGESTERON BİYOSENTEZİ ve MOLEKÜLER KONTROL MEKANİZMASI

Year 2019, Volume: 10 Issue: 3, 125 - 134, 30.12.2019

Ruhi Kabakçı Ayşe Arzu Yiğit

Abstract

Yirmi
bir gün süren düzenli östrus siklusu ile yıl boyu üreme aktivitesi gösterebilen
ineklerde korpus luteum (KL)’un önemli bir yeri bulunmaktadır. Ovulasyonla
yumurta hücresinin atılmasından hemen sonra, folikül enkazının bulunduğu yerde
oluşmaya başlayan KL, östrus siklusunun en uzun dönemi olan diöstrus fazında
varlığını sürdürmektedir. Korpus luteumun en önemli ve temel görevi progesteron
(P4) sentezlemektedir. Bu görevi folikül duvarındaki Granuloza ve Teka
hücrelerinin luteinleştirici hormon (LH) uyarımı ile farklılaşmasıyla meydana
gelen büyük ve küçük luteal hücreler gerçekleştirmektedir. Steroidojenik
enzimler aracılığıyla kolesterolden sentezlenen progesteronun, östrus
siklusunun düzenlenmesi ve gebeliğin devamlığını sağlama gibi önemli görevleri
bulunmaktadır. Hazırlanmış olan bu derlemede, inek luteal hücrelerinde meydana
gelen P4 biyosentezi ve sentezin moleküler kontrol mekanizması ile bu
aşamalarda rol oynayan sitokrom p450s (CYP11A1), steroidojenik akut düzenleyici
(StAR) protein, 3-Hidroksisteroit dehidrojenaz (3β-HSD) gibi steroidojenik
enzimler hakkında bilgi verildi. Bu moleküler mekanizmaların ayrıntılarının
bilinmesi ile, önemli ekonomik değeri bulunan ve sağlıklı bir üreme sistemine
sahip olması gereken ineklerde, üreme fizyolojisinin daha iyi anlaşılacağı
düşünülmektedir.

Keywords

İnek Progesteron sentezi Sitokrom p450s StAR Üreme 3β-HSD

References

  • Alaçam, E. (2010). Evcil hayvanlarda doğum ve infertilite, 7th (ed.), Ankara, Turkey: Medisan.
  • Alila, H., Dowd, J., Corradino, R., Harris, W., ve Hansel, W. (1988). Control of progesterone production in small and large bovine luteal cells separated by flow cytometry. Journal of Reproduction and Fertility, 82(2), 645-655.
  • Alila, HW., ve Dowd, JP. (1991). The control of corpus luteum function in domestic ruminants. Oxford Reviews of Reproductive Biology, 13, 203-237.
  • Azhar, S., ve Reaven, E. (2002). Scavenger receptor class bi and selective cholesteryl ester uptake: Partners in the regulation of steroidogenesis. Molecular and Cellular Endocrinology, 195(1), 1-26.
  • Ball, PJH., ve Peters, AR. (2007). Reproduction in cattle, 3rd ed. (ed.), Australia: Blacjwell Publishing.
  • Bao, B., ve Garverick, HA. (1998). Expression of steroidogenic enzyme and gonadotropin receptor genes in bovine follicles during ovarian follicular waves: A review. Journal of Animal Science, 76(7), 1903-1921.
  • Brown, MS., ve Goldstein, JL. (1986). A receptor-mediated pathway for cholesterol homeostasis. Science, 232(4746), 34-47.
  • Cameron, JL., ve Stouffer, RL. (1982). Gonadotropin receptors of the primate corpus luteum. Ii. Changes in available luteinizing hormone-and chorionic gonadotropin-binding sites in macaque luteal membranes during the nonfertile menstrual cycle. Endocrinology, 110(6), 2068-2073.
  • Carr, BR., Macdonald, PC., ve Sımpson, ER. (1980). The regulation of de novo synthesis of cholesterol in the human fetal adrenal gland by low density lipoproteinand adrenocorticotropin. Endocrinology, 107(4), 1000-1006.
  • Chegini, N., Lei, Z., Rao, CV., ve Hansel, W. (1991). Cellular distribution and cycle phase dependency of gonadotropin and eicosanoid binding sites in bovine corpora lutea. Biology of Reproduction, 45(3), 506-513.
  • Davidson, AP., ve Stabenfeldt, GH. (2007). Reproduction and lactation, In Cunningham, JG., ve Klein, BG (Cunningham, JG., ve Klein, BG(Cunningham, JG., ve Klein, BGs.), Cunningham's textbook of veterinary physiology. 4th (ed.), St. Louis, MO: Saunders, an imprint of Elsevier Inc; pp. 465-474.
  • Davis, JS. (1991). Interactions among the camp and ip 3/dag intracellular signaling systems in bovine luteal cells, InSignaling mechanisms and gene expression in the ovary. Springer; pp. 39-53.
  • Goravanahally, MP., Sen, A., Inskeep, EK., ve Flores, JA. (2007). Pkcepsilon and an increase in intracellular calcium concentration are necessary for pgf2alpha to inhibit lh-stimulated progesterone secretion in cultured bovine steroidogenic luteal cells. Reproductive Biology and Endocrinology, 5(1), 37.
  • Graham, JD., ve Clarke, CL. (1997). Physiological action of progesterone in target tissues 1. Endocrine Reviews, 18(4), 502-519.
  • Grummer, R., ve Carroll, D. (1988). A review of lipoprotein cholesterol metabolism: Importance to ovarian function. Journal of Animal Science, 66(12), 3160-3173.
  • Hansel, W., Alila, HW., Dowd, JP., ve Yang, X. (1987). Control of steroidogenesis in small and large bovine luteal. Cells. Australian Journal of Biological Sciences, 40(3), 331-348.
  • Hartung, S., Rust, W., Balvers, M., ve Ivell, R. (1995). Molecular cloning and in vivo expression of the bovine steroidogenic acute regulatory protein. Biochemical and Biophysical Research Communications, 215(2), 646-653.
  • Hu, J., Zhang, Z., Shen, W-J., ve Azhar, S. (2010). Cellular cholesterol delivery, intracellular processing and utilization for biosynthesis of steroid hormones. Nutrition & metabolism, 7, 47-47.
  • Johnson, WJ., Phillips, MC., ve Rothblat, GH. (1997). Lipoproteins and cellular cholesterol homeostasis, In Bittman, R (Bittman, R),Bittman, Rs.), Cholesterol. Springer; pp. 235-276.
  • Krisans, SK. (1996). Cell compartmentalization of cholesterol biosynthesisa. Annals of the New York Academy of Sciences, 804(1), 142-164.
  • Milvae, R., ve Hansel, W. (1980). The effects of prostacyclin (pgi2) and 6-keto-pgf1α on bovine plasma progesterone and lh concentrations. Prostaglandins, 20(4), 641-647.
  • Milvae, R., ve Hansel, W. (1983). Prostacyclin, prostaglandin f2α and progesterone production by bovine luteal cells during the estrous cycle. Biology of Reproduction, 29(5), 1063-1068.
  • Miyamoto, A., Kshirasuna, T., Bollwein, H., ve Schams, D. (2011). Regulation of corpus luteum development and maintenance: Specific roles of angiogenesis and action of prostaglandin f2α. Reprod Domest Anim, 289.
  • Nishizuka, Y. (1984). Turnover of inositol phospholipids and signal transduction. Science, 225(4668), 1365-1370.
  • Nishizuka, Y. (1986). Studies and perspectives of protein kinase c. Science, 233(4761), 305-312.
  • Niswender, GD. (2002). Molecular control of luteal secretion of progesterone. Reproduction, 123(3), 333-339.
  • Niswender, GD., Juengel, JL., Silva, PJ., Rollyson, MK., ve Mcintush, EW. (2000). Mechanisms controlling the function and life span of the corpus luteum. Physiological Reviews, 80(1), 1-29.
  • Norman, AW., ve Litwack, G. (1997). Hormones, 3rd (ed.), USA: Academic Press.
  • Papadopoulos, V., Baraldi, M., Guilarte, TR., Knudsen, TB., Lacapère, J-J., Lindemann, P., Norenberg, MD., Nutt, D., Weizman, A., ve
  • Zhang, M-R. (2006). Translocator protein (18 kda): New nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. Trends in Pharmacological Sciences, 27(8), 402-409.
  • Papadopoulos, V., ve Brown, AS. (1995). Role of the peripheral-type benzodiazepine receptor and the polypeptide diazepam binding inhibitor in steroidogenesis. The Journal of steroid biochemistry and molecular biology, 53(1-6), 103-110.
  • Reece, WO., Erickson, HH., Goff, JP., ve Uemura, EE. (2015). Dukes' physiology of domestic animals, 13th (ed.), USA: Am Vet Med Assoc.
  • Rekawiecki, R., Kowalik, M., Slonina, D., ve Kotwica, J. (2008). Regulation of progesterone synthesis and action in bovine corpus luteum. Journal of Physiology and Pharmacology, 59(9), 75-89.
  • Richards, JS., Russell, DL., Ochsner, S., ve Espey, LL. (2002). Ovulation: New dimensions and new regulators of the inflammatory-like response. Annual Review of Physiology, 64(1), 69-92.
  • Romani, F., Tropea, A., Scarinci, E., Dello Russo, C., Lisi, L., Catino, S., Lanzone, A., ve Apa, R. (2013). Endocrine disruptors and human corpus luteum: In vitro effects of phenols on luteal cells function. Journal of Environmental Science and Health. Part C: Environmental Carcinogenesis & Ecotoxicology Reviews, 31(2), 170-180.
  • Rosenson, RS., Brewer Jr, HB., Davidson, WS., Fayad, ZA., Fuster, V., Goldstein, J., Hellerstein, M., Jiang, X-C., Phillips, MC., ve Rader, DJ. (2012). Cholesterol efflux and atheroprotection: Advancing the concept of reverse cholesterol transport. Circulation, 125(15), 1905-1919.
  • Schatten, H., ve Constantinescu, GM. (2007). Comparative reproductive biology, 1st: Wiley Online Library.
  • Seedorf, U., Ellinghaus, P., ve Nofer, JR. (2000). Sterol carrier protein-2. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids, 1486(1), 45-54.
  • Sewer, MB., ve Li, D. (2008). Regulation of steroid hormone biosynthesis by the cytoskeleton. Lipids, 43(12), 1109.
  • Shen, W-J., Patel, S., Natu, V., Hong, R., Wang, J., Azhar, S., ve Kraemer, FB. (2003). Interaction of hormone-sensitive lipase with steroidogeneic acute regulatory protein facilitation of cholesterol transfer in adrenal. Journal of Biological Chemistry, 278(44), 43870-43876.
  • Skarzynski, DJ., ve Okuda, K. (2010). Inter- and intra-cellular mechanisms of prostaglandin f2alpha action during corpus luteum regression in cattle. Society of Reproduction and Fertility Supplement, 67, 305-324.
  • Stancu C, SA. (2001). Statins: Mechanism of action and effects. Journal of Cellular and Molecular Medicine, 5(04), 378-387.
  • Stocco, C., Telleria, C., ve Gibori, G. (2007). The molecular control of corpus luteum formation, function, and regression. Endocrine Reviews, 28(1), 117-149.
  • Stone, D., ve Hechter, O. (1954). Studies on acth action in perfused bovine adrenals: The site of action of acth in corticosteroidogenesis. Archives of Biochemistry and Biophysics, 51(2), 457-469.
  • Tsang, PC. (2016.) Contrıbutıons of the ovary to fertılıty in daıry cows. slideplayer, Erişim adresi: [https://slideplayer.com/slide/10687536/], Erişim tarihi: 14.11.2019.
  • Wade, RL., Van Andel, RA., Rice, SG., Banka, CL., ve Dyer, CA. (2002). Hepatic lipase deficiency attenuates mouse ovarian progesterone production leading to decreased ovulation and reduced litter size. Biology of Reproduction, 66(4), 1076-1082.
  • Walsh, SW., Mehta, JP., Mcgettigan, PA., Browne, JA., Forde, N., Alibrahim, R., Mulligan, F., Loftus, B., Crowe, MA., ve Matthews, D. (2012). Effect of the metabolic environment at key stages of follicle development in cattle: Focus on steroid biosynthesis. Physiological Genomics, 44(9), 504-517.
  • Yılmaz, B. (1999). Hormonlar ve üreme fizyolojisi, 1st (ed.), Ankara: Feryal Matbaacılık.
There are 48 citations in total.

Details

Primary Language Turkish
Subjects Veterinary Sciences
Journal Section Review
Authors

Ruhi Kabakçı 0000-0001-9131-0933

Ayşe Arzu Yiğit 0000-0001-5837-6877

Publication Date December 30, 2019
Acceptance Date December 19, 2019
Published in Issue Year 2019 Volume: 10 Issue: 3

Cite

APA Kabakçı, R., & Yiğit, A. A. (2019). İNEKLERDE LUTEAL PROGESTERON BİYOSENTEZİ ve MOLEKÜLER KONTROL MEKANİZMASI. Veteriner Farmakoloji Ve Toksikoloji Derneği Bülteni, 10(3), 125-134.
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