Differential inhibition of naringenin on human and rat cytochrome P450 2E1 activity.

Cytochrome P450 2E1 (CYP2E1) has been proposed as a molecular target in oxidative stress-associated metabolic diseases. Rats are chosen as model organisms in most experiments studying CYP2E1-related toxicity; however, the human relevance of these results remains unclear. To describe differences in catalysis and inhibition between human and rat CYP2E1, recombinant human and rat CYP2E1 enzymes were treated with different concentrations of naringenin (NAR, 10 nM - 1 mM), and inhibition parameters were calculated. Interspecies differences in the catalytic efficiency for O-demethylation of 7-methoxy-4-(trifluoromethyl)coumarin were revealed (45-fold higher in human CYP2E1 than in the rat enzyme). Additionally, differences in the potency of inhibition of NAR were found (absolute half inhibitory concentration, IC50 = 204 ± 28 and 69 ± 4 µM; inhibition constant, Ki = 9 ± 2 and 161 ± 20 µM in human and rat CYP2E1, respectively). Although NAR exhibited a noncompetitive mechanism of inhibition of both CYP2E1 enzymes, this compound is an irreversible inhibitor of rat CYP2E1 and a reversible inhibitor of the human enzyme. Molecular docking suggested that differences in the potency of inhibition and time dependence between species could be attributable to the differential interactions of NAR with access channels to the CYP2E1 catalytic site. These results highlight the importance of finding the appropriate model to improve the predictability of animal-based assays for human risk assessment.

Time-caloric restriction inhibits the neoplastic transformation of cirrhotic liver in rats treated with diethylnitrosamine.

Hepatocellular cancer is the most common type of primary liver cancer. Cirrhosis is the main risk factor that generates this malady. It has been proven that caloric restriction protocols and restricted feeding schedules are protective in experimental carcinogenic models. We tested the influence of a time-caloric restriction protocol (2 h of food access during the daytime for 18 weeks) in an experimental model of cirrhosis-hepatocarcinoma produced by weekly administration of diethylnitrosamine. Our results indicate that time-caloric restriction reduced hepatomegaly and prevented the increase in blood leukocytes promoted by diethylnitrosamine. Strikingly, time-caloric restriction preserved functional and histological characteristics of the liver in fibrotic areas compared to the cirrhotic areas of the Ad Libitum-fed group. Tumoural masses in the restricted group were well differentiated; consider a neoplastic or early stage of HCC. However, time-caloric restriction enhanced collagen deposits. With regard to the cancerous process, food restriction prevented systemic inflammation and an increase in carcinoembryonic antigen, and it favoured the occurrence of diffuse multinodular tumours. Histologically, it prevented hepatocyte inflammation response, the regenerative process, and neoplastic transformation. Time-caloric restriction stimulated circadian synchronization in fibrotic and cancerous liver sections, and it increased BMAL1 clock protein levels. We conclude that time-caloric restriction prevents fibrosis from progressing into cirrhosis, thus avoiding chronic inflammation and regenerative processes. It also prevents, probably through circadian entrainment and caloric restriction, the neoplastic transformation of tumoural lesions induced by diethylnitrosamine.

Effect of [Cu(4,7-dimethyl-1,10-phenanthroline)(acetylacetonato)]NO3, Casiopeína III-Ea, on the activity of cytochrome P450.

Casiopeína III-Ea (Cas III-Ea(1)) is a copper complex with antiproliferative and antitumor activities, designed to act via alternative mechanisms of action different from Cisplatin. This compound has also been well characterized in preclinical test and pharmacokinetic analysis, being a good candidate for clinical phases. Since very little is known about the processes of biotransformation of therapeutic metal based drugs, this paper report the first approach to the study of the interaction between metal complex Cas III-Ea and cytochromes P450 with the aim to find out possible biotransformation pathways for this complexes and feasible drug-drug interactions. Results showed that Cas III-Ea is a strong irreversible competitive inhibitor of CYP1A1 (IC50 = 7.5 ± 1.0 µM; Ki = 240 nM). The magnitude of values indicate that it is necessary to be taken into account such effect when analyzing possible drug interactions with these new drugs in order to prevent adverse reactions derived from this inhibition.

Regulation of Human Cytochrome P4501A1 (hCYP1A1): A Plausible Target for Chemoprevention?

Human cytochrome P450 1A1 (hCYP1A1) has been an object of study due to its role in precarcinogen metabolism; for this reason it is relevant to know more in depth the mechanisms that rule out its expression and activity, which make this enzyme a target for the development of novel chemiopreventive agents. The aim of this work is to review the origin, regulation, and structural and functional characteristics of CYP1A1 letting us understand its role in the bioactivation of precarcinogen and the consequences of its modulation in other physiological processes, as well as guide us in the study of this important protein.