Zein Shaban Ibrahim

The induction of cytochrome P450 1A1 by sudan dyes.

Azo dyes form a major class of chemically related compounds that are ubiquitous in foods, paints, printing inks, cosmetics, and also used as biological stains in histological and histopathological laboratories and clinics. Sudan I, sudan III, and sudan IV have been classified as category 3 carcinogens by International Agency for Research on Cancer. In this study, we investigated the difference between these three sudan dyes in induction of CYP1A1. We intraperitoneally treated Wistar rats with each of the three sudan dyes (I, III, and IV) for 3 days. Treatment of Wistar rats with sudan I produced the highest induction of CYP1A1 protein and mRNA whereas treatment of Wistar rats with sudan III produced about two third of CYP1A1 protein and mRNA than induced by sudan I. Furthermore, treatment of Wistar rats with sudan IV produced the lowest induction of CYP1A1 protein and mRNA which is about two third of that induced with sudan III treatment. We further investigated the effect of these sudan dyes on CYP1A1 transcription through investigating the xenobiotic response element (XRE) reporter activity in HepG2. The XRE reporter activity study showed the same trend of activity of sudan dyes comparable to the effects on CYP1A1 mRNA and protein. Immunohistochemical study revealed a differential pattern of distribution of CYP1A1 protein in rat liver among the three sudan dyes, apparent in the centrilobular and midzonal region with sudan III, progressing to panlobular with sudan I, whereas sudan IV showed a reversal of pattern of induction with the most intense staining in the periportal region. Our results suggest that there is an inverse relationship between the molecular size of the three sudan dyes and their ability to induce CYP1A1.

Molecular mechanism of hepato-renal protection of camel milk against oxidative stress-perturbations

Possible molecular mechanism of camel milk protection of liver and kidney against oxidative stress generated by CCl4 injection was investigated. Rats injected with carbon tetrachloride (CCl4) showed upregulation of the mRNA expression of hepatic IL-6 and renal IL-1β, TGF- β1, SREBP-1c and caspase-6 and down-regulation of anti-oxidative enzymes SOD, GST and CAT in addition to hepatocellular vacuolation, mononuclear cell infiltration and sinusoidal dilatation and renal glomerular atrophy, capsular space expansion, and adhesion between visceral and parietal layers of Bowmans capsule. Camel milk supplementation prior and with CCl4 injection to rats attenuated CCl4-induced hepatic and renal inflammatory cytokines (IL-6, IL-1β, TGF- β1 SREBP-1c and caspase-6), upregulated CCl4-suppressed anti-oxidative markers (SOD, GST and CAT) and induced protective and regenerative mechanism (EPO and IL-10). Additionally camel milk protected the liver and kidney from CCl4-induced histopathological changes. These results showed the mechanism of camel milk protection of liver and kidney against CCl4-generated oxidative stress and injuries. These findings may support the beneficial use of camel milk as therapeutic adjuvant with drugs that always associated with production of oxidative stress that injured liver and kidneys as anti-tumor drugs as Cisplatin.

Effects of camel milk on drug metabolising cytochrome P450 enzymes expressions in rats

Cytochrome P450 (CYPs) constitutes the major enzyme family capable of catalysing the oxidative biotransformation of most drugs. These are affected by a large number of factors including environmental elements. Widely practiced drinking of camel milk as a nutrient, therapy for some disease or even adjuvant with some drugs make it mandatory to investigate the possible CYPs modulator effects of camel milk. Forty-eight male Wistar rats were divided into 6 groups of 8 rats each. Groups were allocated as control, Camel milk (CM) treated, Sudan III (S.III) treated, S.III +CM, Phenobarbital (PB) or PB+CM.

Clofibric acid induces hepatic CYP 2B1/2 via constitutive androstane receptor not via peroxisome proliferator activated receptor alpha in rat

Peroxisome proliferator activated receptor α (PPARα) ligands, fibrates used to control hyperlipidemia. We demonstrated CYP2B induction by clofibric acid (CFA) however, the mechanism was not clear. In this study, HepG2 cells transfected with expression plasmid of mouse constitutive androstane receptor (CAR) or PPARα were treated with CFA, phenobarbital (PB) or TCPOBOP. Luciferase assays showed that CFA increased CYP2B1 transcription to the same level as PB, or TCPOBOP in HepG2 transfected with mouse CAR But failed to induce it in PPARα transfected cells. CYP2B expressions were increased with PB or CFA in Wistar female rats (having normal levels of CAR) but not in Wistar Kyoto female rats (having low levels of CAR). The induction of CYP2B by PB or CFA was comparable to nuclear CAR levels. CAR nuclear translocation was induced by CFA in both rat strains. This indicates that fibrates can activate CAR and that fibrates-insulin sensitization effect may occur through CAR, while hypolipidemic effect may operate through PPARα. Graphical Abstract A transcriptional proof of the mechanism through which clofibric acid induce CYP2B through constitutive androstane receptor (CAR) not through PPARα