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 µM 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.

Effect of rifampicin and erythromycin on the initiation of galactose induced cataract in rats

“…Previous studies[45] quote that the inducers have significantly caused early initiation of cataract, but in the present study the inducer rifampicin did not. But the inhibitors have significantly delayed the occurrence of cataract in the present study which is consistent with the results of the previous studies.…”

“…It has thus been hypothesized that by using enzyme inducer, pioglitazone, and inhibitor, diltiazem and nifedipine, the activity of aldose reductase and formation of cataract can be altered. [45] However Jaykaran[6] and Mahajan et al . [7] have questioned the inclusion of pioglitazone, a weak inducer of CYP enzyme.…”

“…Similarly, in the study by Patel et al .,[5] pioglitazone was used, but the CYP inhibitor used was nifedipine. However, the choice of the test drug pioglitazone is questionable, as it is a weak inducer of CYP.…”

“…But the inhibitors have significantly delayed the occurrence of cataract in the present study which is consistent with the results of the previous studies. [45] It is therefore, not possible to extrapolate results of one enzyme inhibitor or inducer to other CYP modulators. Therefore further investigations using a variety of CYP modulators are needed to identify the pharmacological profile of CYP modulators on cataractogenesis in large scale.…”

Inferences from targeting CYP450 modulation to decrease the risk of induced cataract in the experimental model?

“…This refers to a well drafted article by Patel et al ., published in a recent issue of Indian Journal of Ophthalmology . [ 1 ] The present study is based on the hypothesis that basic pathology for cataract is conversion of excess glucose to sorbitol (which can cause cataract) by enzyme aldose reductase using NADPH as a cofactor, and electron transfer from NADPH that depends on the cytochrome P450 system (CYP450). It was postulated that by inducing or inhibiting cytochrome, one can alter the activity of aldose reductase, formation of sorbitol, and hence modulate the occurrence of cataract.…”