Targeting CYP450 modulation to decrease the risk of induced cataract in the experimental model

Abstract

Background: Diabetes is one of the major causes of cataract. Some drugs prescribed for the treatment of diabetes are the modulators of CYP450, which may alter the risk of cataract.

Objective: To study the effect of CYP450 modulation in galactosemic cataract.

Materials and methods: Male Sprague-Dawley suckling rats were allotted to four groups (n = 6), as follows: Group 1: Normal control, Group 2: Galactose control, Group 3: CYP450 inhibitor pretreated and Group 4: CYP450 inducer pretreated. Cataract was induced in animals of all groups except group 1 by feeding them galactose (50%), 21 days after parturition. From the eighteenth day of life, CYP450 inhibitor (nifedipine; 8.1 mg/kg) and CYP450 inducer (pioglitazone; 3.8 mg/kg) were given orally to groups 3 and 4, respectively. The maturation pattern of the cataract was observed by an operating microscope, every third day. Biochemical changes in the lenses of all groups, for example, CYP450 activity expressed as ΅M NADPH oxidized / unit time, alterations in the levels of total proteins, soluble proteins, and reduced glutathione (GSH) following the induction of cataract, were estimated.

Results: The microscopic examination of the lenses indicated that CYP450 inhibitor pre-treatment delayed (fourteenth day) the occurrence of cataract, while CYP450 inducer pretreatment demonstrated an early (ninth day) cataract as compared to galactose control rats (twelfth day). A significant decrease and increase in CYP450 activity was observed with the CYP450 inhibitor and inducer pre-treatment, respectively. There was no alteration in the GSH level, but a significant increase in total and soluble protein was found in groups 3 and 4 as compared to group 2.

Conclusion: CYP450 may have a role in the initiation of cataract without any effect on the maturation pattern, as revealed by the delayed occurrence of cataract with the CYP450 inhibitor and an early onset of cataract with the CYP450 inducer.

Figure 1

Microscopic Evaluation of Cataract. Photographs of lenses using Operating Microscope (OM-18; magnification 6X). (Group 1) Normal control; (Group 2) Galactose control; (Group 3) CYP450 inhibitor-nifedipine pretreated galactosemic lens; (Group 4) CYP450 inducer-pioglitazone pretreated galactosemic lens

Figure 2

Plots of relative protein contents from (Group 1) Normal control; (Group 2) Galactose control; (Group 3) CYP450 inhibitornifedipine pretreated galactosemic lens; and (Group 4) CYP450 inducer-pioglitazone pretreated galactosemic lens. The vertical lines inside the plot represent the SEM. P ≤ 0.05: *versus group 1, #versus group 2

Figure 3

Plots of CYP450 activity expressed as µM NADPH +/5 minutes from (Group 1) Normal control; (Group 2) Galactose control; (Group 3) CYP450 inhibitor-nifedipine pretreated galactosemic lens;(Group 4) CYP450 inducer-pioglitazone pretreated galactosemic lens. The vertical lines inside the plots represent the SEM. P ≤ 0.05: *versus group 1, #versus group 2

Figure 4

Plot of reduced glutathione content of the lens from (Group 1) Normal control; (Group 2) Galactose control; (Group 3) CYP450 inhibitor-nifedipine pretreated galactosemic lens; and (Group 4) CYP450 inducer-pioglitazone pretreated galactosemic lens. The vertical lines inside the plots represent the SEM. P ≤ 0.05: *versus group 1, #versus group 2