No abstract

Smoking has the strongest impact on CYP1A2 activity, while gender and haplotype H4 showed marginal effects. The influence of the -163C>A polymorphism on CYP1A2 activity in smokers suggests an effect on the inducibility of the enzyme.

Endogenous nitric oxide (NO) is an important mediator in the processes that control biological clocks and circadian rhythms. The present study was designed to elucidate if NO synthase (NOS) activity in the brain, kidney, testis, aorta, and lungs and plasma NOx levels in mice are controlled by an endogenous circadian pacemaker. Male BALB/c mice were exposed to two different lighting regimens of either light-dark 14:10 (LD) or continuous lighting (LL). At nine different equidistant time points (commencing at 09:00h) blood samples and tissues were taken from mice. The plasma and tissue homogenates were used to measure the levels of NO2 + NO3- (NOx) and total protein. The NOx concentrations were determined by a commercial nitric oxide synthase assay kit, and protein content was assessed in each homogenate tissue sample by the Lowry method. Nitric oxide synthase activity was calculated as pmol/mg protein/h. The resulting patterns were analyzed by the single cosinor method for pre-adjusted periods and by curve-fitting programs to elucidate compound rhythmicity. The NOS activity in kidneys of mice exposed to LD exhibited a circadian rhythm, but no rhythmicity was detected in mice exposed to LL. Aortic NOS activity displayed 24h rhythmicity only in LL. Brain, testis, and lung NOS activity and plasma NOx levels displayed 24h rhythms both in LD and LL. Acrophase values of NOS activity in brain, kidney, testis, and lungs were at midnight corresponding to their behavioral activities. Compound rhythms were also detected in many of the examined patterns. The findings suggest that NOS activity in mouse brain, aorta, lung, and testis are regulated by an endogenous clock, while in kidney the rhythm in NOS activity is synchronized by the exogenous signals.

Drug interactions have been reported between 5-fluorouracil and cytochrome P450 2C9 (CYP2C9) substrates, S-warfarin and phenytoin. This study was performed to determine the influence of 5-fluorouracil on cytochrome P450 2C9 (CYP2C9) activity in colorectal cancer patients (nΩ17) receiving 5-fluorouracil. Losartan was used as a marker to assess CYP2C9 activity. Losartan and its CYP2C9 dependent metabolite, E-3174, were determined in urine. The ratios of urinary losartan/E-3174 before and after the 5-fluorouracil treatment were compared for each patient. Genotyping was performed to detect the CYP2C9*2 and CYP2C9*3. At the end of the first cycle of 5-fluorouracil, losartan/E-3174 ratio was increased by 28.0% compared to the pre-treatment values (PΩ0.15). In five patients recruited for phenotyping after three 5-fluorouracil cycles, the metabolic ratio was increased significantly by 5.3 times (PΩ0.03). The results suggest that in most patients 5-fluorouracil inhibited CYP2C9 activity. This inhibition was more pronounced when the total administered dose increased. This finding may help explain the mechanism of interaction between 5-fluorouracil and CYP2C9 substrates.5-Fluorouracil is a fluorinated pyrimidine analogue used in the treatment of a variety of solid tumours including gastrointestinal, breast, head and neck cancer (Rich et al. 2004). The cytotoxicity of 5-fluorouracil is mainly due to the formation of fluoro-deoxyuridine-monophosphate metabolite, which inhibits thymidylate synthetase and incorporates into ribonucleic acid (Rich et al. 2004). 5-Fluorouracil has a rather short elimination half-life in plasma and is mostly eliminated by dihydropyrimidine dehydrogenase (Gonzalez & Fernandez-Salguero 1995). Due to many complications during chemotherapy, many other drugs are co-administrated during treatment with 5-fluorouracil. Increasing number of drug-drug interactions between warfarin and 5-fluorouracil-based chemotherapies have been reported. These interactions result in bleeding complications due to the prolongation of prothrombin time (Brown 1997(Brown & 1999Kolesar et al. 1999). 5-Fluorouracil has also been reported to interact with phenytoin, resulting in elevated phenytoin plasma concentrations and neurotoxic side effects (Gilbar & Brodribb 2001;Konishi et al. 2002;Rosemergy & Findlay 2002;Brickell et al. 2003). Both S-warfarin and phenytoin are established CYP2C9 substrates (Lee et al. 2002). The mechanism of these interactions is unclear. Available evidence from case reports and in vitro studies in liver microAuthor for correspondence: Umit Yasar, Hacettepe University, Faculty of Medicine, Department of Pharmacology, 06100 Sihhiye, Ankara, Turkey (fax π90 312 3105312, e-mail uyasar/hacettepe.edu. tr).somes suggests that the interaction is not due to a competitive inhibition of CYP2C9 (Brown 1999;Park & Kim 2003). The effect of 5-fluorouracil on in vivo CYP2C9 activity in man has not been studied. Prospective clinical studies are needed to clarify the mechanism of the interaction between the su...

We investigated the day-night differences in intestinal oxidativeinjury and the inflammatory response following total body (TB) or abdominopelvic (AP) irradiation, and the influence of melatonin administration on tissue injury induced by radiation. Rats (male Wistar, weighing 220-280 g) in the irradiated groups were exposed to a dose of 8 Gy to the TB or AP region in the morning (resting period -1 h after light onset) or evening (activity span -13 h after light onset). Vehicle or melatonin was administered immediately before, immediately after and 24 h after irradiation (10, 2.0 and 10 mg/kg, ip, respectively) to the irradiated rats. AP (P < 0.05) and TB (P < 0.05) irradiation applied in the morning caused a significant increase in thiobarbituric acid reactive substance (TBARS) levels. Melatonin treatment in the morning (P < 0.05) or evening (P < 0.05) decreased TBARS levels after TB irradiation. After AP irradiation, melatonin treatment only in the morning caused a significant decrease in TBARS levels (P < 0.05). Although we have confirmed the development of inflammation after radiotherapy by histological findings, neither AP nor TB irradiation caused any marked changes in myeloperoxidase activity in the morning or evening. Our results indicate that oxidative damage is more prominent in rats receiving TB and AP irradiation in the morning and melatonin appears to have beneficial effects on oxidative damage irrespective of the time of administration. Increased neutrophil accumulation indicates that melatonin administration exerts a protective effect on AP irradiation-induced tissue oxidative injury, especially in the morning.