Effects of Quinazolinones on the Development of BALB/c Mice Embryonic Kidneys

Document Type : Original Article


1 Developmental Biology, Animal Sciences, Faculty of Biological Sciences, Shahid-Beheshti University, Tehran, Iran

2 Department of Pathology, Medical School, Shahid- Beheshti University, Tehran, Iran


Quinazolinones are heterocyclic components (able to form cyclized compounds) which have several medical effects such as anti-malarial, spasmolytic, anti-microbial, sedative, etc. They are also known for their fungicidal properties, inhibition of tyrosine-kinase and DNA repair enzyme poly (ADP-ribose) polymerase (PARP) and are also effective in treatment of cancer, diabetes, and parkinsonism complications.
Materials and Methods
In this study, for the first time different aspects of developmental effects of two new Quinazolinone components (QPPE and QEPE), on kidneys of BALB/c mice embryos were investigated. Pregnant BALB/c mice were divided into four groups of control (n=30), sham (n=30), experimental 1 (n=30) and experimental 2 (n=30). Control mice remained intact, sham and two experimental groups received 0.05% methyl cellulose and 100 mg/kg/body weight (most effective dose) of QPPE and QEPE, intraperitoneally (IP), on day 10th of gestation. Kidneys were removed by c-sections, stained with H&E, PAS, trichrome, reticholin and jones staining. Some embryonic kidneys were prepared for measurements of level of alkaline phosphatase and TEM studies.
Light and TEM microscopes, and level of enzyme surveys demonstrated that QPPE and QEPE are toxic components, creating protrusions at the surface of convoluted proximal tubules, protein casts, renal necrotic cells, pseudothyroidezation, mitochondria degeneration, hyperemia, glomeruli hypertrophy, widening of renal spaces, vacuolization, as well as decrease in the number of brush border villi and level of alkaline phosphatase.
By being teratogens and toxins, these two new derivatives affected development of embryonic kidneys at histological, biochemical and intracellular levels; QEPE had more effects and convoluted proximal tubules were more sensitive than convoluted distal tubules.


1.Derelanko MJ, Hollinger MA. Handbook of toxicology. Boca Raton: CRC Press; 2002.
2.Gardella JR, Hill JA. Environmental toxins associated with recurrent pregnancy loss. Semin Repro Med 2000; 18:407-424.
3.Fowden AL, Ward JW, Wooding FPB, Forhead AJ, Constancia M. Programming placental nutrient transport capacity. J Physiol 2006; 572:5-15.
4.Coan PM, Angiolini E, Sandovici I, Burton GJ, Constancia M, Fowden AL. Adaptations in placental nutrient transfer capacity to meet fetal growth demands depend on placental size in mice. J Physiol 2008; 15:4567-4576.
5.Goodlett CR, Horn KH, Zhou FC. Alcohol teratogenesis: mechanisms of damage and strategies for intervention. Exp Biol Med 2005; 230:394-406. 
6.Shams Lahijani M, Ahmadzadeh F, Dabiri M. Teratogenic effects of a new derivative of quinazolinone on the development of BALB/c mice embryos,on days 9,10 and 11 of gestation. Iran J Sci Technol 2006; 30Ai:1- 8.
7.Shams Lahijani M, Aounegh R. Teratogenic effects of quinazolinone on BALB/c mice fetuses. J Med Sci Res 2007; 1:25-30.
8.Shams Lahijani M, Rajabi H, Etemad S, Fadavi Eslam M. Qualitative and quantitative analysis of the effects of quinazolinones on internal organs of newborn BALB/c mice. Iran J Basic Med Sci 2009; 12:112-120.
9.Shams Lahijani M, Hamidi S. Birth Defects caused by quinazolinones in BALB/c mice stomachs. ISPD, Vancouver, Canada, 2008; 1- 4.
10.Shams Lahijani M, Moayer F, Shah Hossein Pour Shoushtary E. Pathological effects of quinazolinones on the brains of newborn BALB/c mice. ESVP, Dubrovnick, Croatia, 2008; 17-21.
11.Estakhr J, Shams Lahijani M. Birth defects in spleen of BALB/c newborns mice treated with quinazolinones. ICBES, Hurghada, Egypt, 2008; 13-16.
12.Abdel-Alim M, El-Shorbag Abdel-Nasser A, El-Gendy Mahmoud A, El-Shareif Hosny AH. Quinazolinone derivatives of biological interest: V. Novel 4(3H)-Quinazolinones with sedative-hypnotic, anticonvulsant and anti-inflammatory activities. Coll Cze Che Comm2008; 58:1963-1968.
13.Jiang S, Zeng Q, Gettayacamin M, Tungtaeng A, Wannaying S, Lim A, et al. Anti-malaria activities and therapeutic properties of febrifugine analogs. Antimicrob Agents Chemother 2005; 49:1169-1176.
14.Refaie FM, Esmat AY, Abdel Gawad SM, Ibrahim AM, Mohamed MA. The anti-hyperlipidemic activities of 4(3H) quinazolinone and two halogenated derivatives in rats. Lipids Health Dis 2005; 4:22-30.
15.Yadav MR, Shirude ST, Parmar A, Balaraman R, Giridhar R. Synthesis and anti-inflammatory activity of 2,3- diaryl-4(3H)-quinazolinones. Chem Heter Com 2006; 42:1038-1045.
16.Dabiri M, Salehi P, Khajavi MS, Mohammadi A. Microwave-assisted one- pot three component synthesis of some new 4(3H)- quinazolinone derivatives. Hetero 2004; 36:1417-1421.
17.Browne MJ, Pitts MW, Pitts RF. Alkaline phosphatase activity in kidneys of glomerular and aglomerular marine teleosts. Biol Bull 1950; 99152-156.
18.Dehghani H, Narisawa S, Millan JL, Hahnel AC. Effects of disruption of the embryonic alkaline phosphatase gene on preimplantation development of the mouse. Dev Dyn 2000; 217:440-448.
19.Sun XM, Li D, Bai ZL, Jin WR. Electrochemical detection of alkaline phosphtase in BALB/c mice fetal liver stromal cells with capillary electrophoresis. Chin Chem Lett 2004; 15:212-213.
20.Gyrd-Hansen N. Alkaline phosphatase histochemistry and early renal cortical damage. Histochem J 1974; 6:199-209.
21.Schmidt U, Schlumpf V, Josch W, Dubach UC. Acute renal failure in the rat after folate intoxication: diagnostic value of lactate dehydrogenase and alkaline phosphatase measurements in serum and urine. Clin Nephrol 1974; 2:106-112.
22.Udobre A, Edoho EJ, Eseyin O, Etim EI. Effect of artemisinin with folic acid on the activities of aspartate amino transferase,alkanine amino transferase and alkaline phosphatase in rat. As Biochem 2009; 4:55-59.
23.Reimer L, Kohl H. Transmission electron microscopy. 5th ed. Springer, 2008.
24.Solhaug MJ, Bolger PM, Jose PA. The developing kidney and environmental toxins. Pediatrics 2004; 113:1084-1091.
25.Bonventre JV, Weinberg JM. Recent advances in the pathophysiology of ischemic acute renal failure. J Am Soc Nephrol 2003; 14:2199-2210.
26.Camp V, Martin P. The role of macrophages in clearing programmed cell death in developing kidney. Anat Embryol 1996; 194:341-348.
27.Markowitza GS, Perazella MA. Drug-induced renal failure:a focus on tubulointerstitial disease. Clin Chim Acta 2005; 351:31-47.
28.Roselli S, Heidet L, Sich M, Henger A, Kretzler M, Gubler MC, et al. Early glomerular filtration defect and severe renal disease in podocin-deficient mice. Mol Cell Biol 2004; 24:550-560.
29.Nony PA, Schnellmann RG. Mechanisms of renal cell repair and regeneration after acute renal failure. J Pharmacol Exp Ther 2003; 304:905-912.
30.Woolf AS, Hillman KA. Unilateral renal agenesis and the congenital solitary functioning kidney: developmental, genetic and clinical perspectives. BJU Int 2007; 99:17-21.
31.Schrier RW. Diseases of the kidney and urinary tract. 8th ed. Vol II, Lippincott Williams & Wilkins, 2006.
32.Doublier S, Ruotsalainen V, Salvidio G, Lupia E, Biancone L, Conaldi P, et al. Nephrin redistribution on podocytes is a potential pathomechanism for proteinuria in patients with primary acquired nephritic syndrome. Am J Pathol 2001; 152:1723-1731.
33.Brady HR, Kone BC, Stromski ME, Zeidel ML, Giebisch G, Gullans SR. Mitochondrial injury: an early event in cisplatin toxicity to renal proximal tubules. Am J Physiol Renal Physiol 1990; 258:1181-1187.
34.Lee SC, Beery JT, Chu FS. Immunohistochemical fate of ochratoxin A in mice. Toxicol Appl Pharmacol 1984; 72:218-227. 
35.Brzoska MM, Kaminski M, Dziki M, Moniuszko-Jakoniuk J. Changes in the structure and function of the kidney of rats chronically exposed to cadmium. Arch Toxicol 2004; 78:226-231.
36.Homma-Takeda S, Takenaka Y, Kumagai Y, Shimojo N. Selective induction of apoptosis of renal proximal tubular cells caused by inorganic mercury in vivo. Envin Toxicol Pharmacol 1999; 7:179-187.
37.Lee H, Shoda R, Krall JA, Foster JD, Selhub J, Rosenberry TL. Folate binding protein from kidney brush border membranes contains components characteristic of a glycoinositol phospholipid anchor. Biochemie 1992; 31:3236-3243.
38.Moser M, Leo O, Hiernaux J, Urbain J. Idiotypic manipulation in mice: BALB/c mice can express the crossreactive idiotype of A/J mice. J Leukoc Biol 2005; 12:32-38.