Long-term systemic toxicity of shikonin derivatives in Wistar rats

Figures & data

Table 1. Body weight changes of the rats in different groups.

	0 day	30 day	60 day	90 day	120 day	150 day	180 day
Normal control (g)	96 ± 2.11	158 ± 3.42	199 ± 3.12	266 ± 5.19	319 ± 5.78	352 ± 6.21	370 ± 7.73
Solvent control (g)	99 ± 3.19	160 ± 5.22	199 ± 4.01	268 ± 6.17	318 ± 5.66	351 ± 5.99	370 ± 6.93
ShD
800 mg/kg (g)	98 ± 3.18	162 ± 4.32	198 ± 5.01	269 ± 5.03	318 ± 5.99	350 ± 5.93	371 ± 6.99
400 mg/kg (g)	101 ± 3.71	162 ± 4.99	204 ± 5.17	271 ± 4.23	318 ± 5.07	352 ± 4.99	369 ± 7.38
200 mg/kg (g)	100 ± 3.22	161 ± 5.29	201 ± 4.31	273 ± 4.54	321 ± 6.16	350 ± 6.08	373 ± 7.27

All p > 0.05.

Table 2. Blood biochemistry examinations of the rats treated with ShD.

Groups	TP g/L	ALB g/L	ALT U/L	ALP U/L	AST U/L	BUN mmol/L	CR umol/L	CHO mmol/L	Glu mmol/L	TBIL umol/L
90 days
Normal control	67.08 ± 4.82	30.61 ± 2.09	46.42 ± 7.35	198.60 ± 63.47	205.30 ± 32.61	7.82 ± 0.75	60.37 ± 8.81	2.21 ± 0.25	7.10 ± 0.98	6.53 ± 0.77
Solvent control	67.19 ± 4.67	29.77 ± 2.70	46.33 ± 8.14	197.50 ± 61.43	201.70 ± 34.91	7.69 ± 0.86	59.27 ± 9.20	2.16 ± 0.35	7.02 ± 1.26	6.78 ± 0.76
ShD
800 mg/kg	67.39 ± 4.30	30.24 ± 2.23	45.89 ± 7.19	200.50 ± 52.85	207.40 ± 53.24	7.83 ± 1.05	61.17 ± 11.07	2.08 ± 0.17	7.06 ± 1.01	6.67 ± 0.79
400 mg/kg	67.05 ± 5.78	31.02 ± 1.97	46.63 ± 7.26	198.50 ± 51.12	201.80 ± 46.93	7.68 ± 0.98	60.33 ± 11.55	2.05 ± 0.18	6.89 ± 0.99	6.71 ± 0.71
200 mg/kg	66.21 ± 4.23	29.99 ± 2.81	45.81 ± 8.94	203.70 ± 73.08	196.10 ± 37.03	7.79 ± 1.16	59.56 ± 13.20	1.99 ± 0.18	6.95 ± 1.14	6.60 ± 0.74
180 days
Normal control	67.01 ± 4.23	30.92 ± 2.47	46.71 ± 10.99	203.66 ± 59.83	190.30 ± 65.35	7.74 ± 0.91	59.38 ± 12.11	2.11 ± 0.19	7.01 ± 0.89	7.15 ± 0.88
Solvent control	66.86 ± 3.18	31.83 ± 2.36	46.38 ± 11.71	202.70 ± 60.25	190.20 ± 62.05	7.61 ± 0.84	60.35 ± 12.02	2.11 ± 0.21	6.82 ± 0.92	7.02 ± 0.90
ShD
800 mg/kg	66.13 ± 5.21	30.68 ± 2.37	46.09 ± 11.74	203.70 ± 60.79	190.40 ± 69.60	7.61 ± 0.69	60.17 ± 10.09	1.95 ± 0.18	7.06 ± 0.94	7.04 ± 0.93
400 mg/kg	65.86 ± 3.74	30.45 ± 2.90	46.10 ± 9.05	205.70 ± 70.17	191.70 ± 60.98	7.73 ± 0.77	58.28 ± 11.50	1.96 ± 0.21	6.92 ± 0.99	6.93 ± 0.59
200 mg/kg	67.36 ± 2.84	30.89 ± 2.04	45.56 ± 7.65	209.50 ± 65.64	192.10 ± 56.03	7.63 ± 0.88	57.87 ± 11.36	0.91 ± 0.20	6.90 ± 1.23	7.06 ± 0.65

TP, total protein; ALB, albumin; ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CR, creatinine; CHO, cholesterol; Glu, glucose; TBIL, total bilirubin. All p > 0.05.

Table 3. Values of blood cell counts of rats treated with ShD.

Groups	WBC × 10^9/L	Lymphocyte (%)	Monocyte (%)	PMNs (%)	RBC × 10^12/L	HGB g/L	MCV	PLT × 10^9/L
90 days
Normal control	11.22 ± 3.12	75.99 ± 5.18	7.02 ± 0.81	16.88 ± 4.78	6.99 ± 0.43	129.64 ± 9.47	39.30 ± 2.01	688.23 ± 147.20
Solvent control	11.10 ± 3.42	76.09 ± 5.29	7.07 ± 0.75	16.84 ± 5.18	7.03 ± 0.52	128.60 ± 9.68	38.33 ± 2.68	680.60 ± 149.90
ShD
800 mg/kg	11.10 ± 3.72	75.87 ± 4.50	7.15 ± 0.79	16.98 ± 4.65	7.01 ± 0.53	131.30 ± 9.82	38.64 ± 3.04	700.10 ± 138.10
400 mg/kg	11.70 ± 3.47	75.69 ± 5.03	7.12 ± 0.69	17.19 ± 4.88	7.04 ± 0.45	134.50 ± 10.30	38.26 ± 2.80	689.00 ± 157.00
200 mg/kg	11.30 ± 2.93	75.18 ± 4.86	7.25 ± 1.07	17.57 ± 4.17	7.02 ± 0.44	131.20 ± 8.35	38.21 ± 1.73	683.10 ± 148.90
180 days
Normal control	11.40 ± 3.15	75.47 ± 5.27	7.22 ± 0.84	16.52 ± 4.88	6.81 ± 0.61	132.75 ± 0.86	38.43 ± 3.77	693.78 ± 128.40
Solvent control	11.60 ± 4.15	76.69 ± 4.92	7.19 ± 0.80	16.12 ± 4.62	6.88 ± 0.66	133.90 ± 0.09	38.26 ± 3.27	688.70 ± 125.90
ShD
800 mg/kg	11.20 ± 2.93	75.40 ± 8.13	7.24 ± 0.64	17.36 ± 7.79	6.85 ± 0.60	132.90 ± 1.05	38.50 ± 2.37	692.80 ± 115.50
400 mg/kg	11.10 ± 5.34	75.74 ± 5.12	7.30 ± 0.76	16.96 ± 4.64	6.83 ± 0.76	132.40 ± 0.95	38.47 ± 2.29	696.10 ± 133.60
200 mg/kg	11.70 ± 4.57	76.46 ± 5.35	7.14 ± 0.88	16.40 ± 5.43	6.89 ± 0.73	132.00 ± 1.02	38.50 ± 2.00	695.50 ± 128.00

WBC, white blood cells; PMNs, polymorphonuclear leucocytes; RBC, red blood cell; HGB, hemoglobin; MCV, mean corpuscular volume; PLT, platelet. All p > 0.05.

Figure 1. Pathological analyses of the vital organs of Wistar rats in different groups. Wistar rats of both ShD treated groups and control groups were kept for 90 or 180 days, then they were sacrificed and the organs were removed for pathological analyses. A to D: sternum, heart, liver and kidney of rats without treatment. E to H: sternum, heart, liver and kidney of rats treated with solvent. I to L: sternum, heart, liver and kidney of rats treated with ShD at the concentration of 800 mg/kg. No significant abnormality and difference were found among the different groups. ☆: bone marrow; ⋆: bone; ▴:myocardial cell; ♦: hepatocyte; •: glomerulus; Δ: renal tubule.