7-Ethoxycoumarin (EC) is widely used as a model substrate for monooxygenase function, its O-deethylation representing cytochrome P450 (P450) activity mainly of 1A but also of 2B isoforms. Reports on investigations of its own capacity to induce or suppress P450 activities, however, have not been found in biomedical literature. To avoid the influence of in vivo pharmacokinetics, studies can well be undertaken with liver slice incubation. Therefore in the present investigation precision-cut rat liver slices from male 43-63-day-old male HAN:Wistar outbred rats were incubated at 30 degrees C in carbogen saturated William's Medium E for 24 h. EC was added previously to final concentrations of 10, 25, 50, 75 or 100 microM. After incubation, homogenate was prepared from slices and used for model reactions (7-ethoxyresorufin O-deethylation [EROD] and 7-pentoxyresorufin O-depentylation [PROD]). EROD, indicating activities of 1A isoforms, was enhanced by incubation with EC at 25 and 50 microM to about doublefold but showed control or lower values at 75 and 100 microM. Incubation with beta-naphthoflavone in comparison led to variable increases (3-5-fold of controls). For PROD as an indicator of the phenobarbital inducible P450 isoforms 2B1 and 2B2 no enhancement was found, but a decrease by incubation with 75 and 100 microM EC. To further investigate the correlation between enzyme activity and gene expression after slice incubation, P450 1A1 mRNA content was measured by RT-PCR. Induced gene expression for 1A1 was seen with different EC concentrations to a variable extent, though not as strong as with BNF. Similar incubation with 4-methyl-7-ethoxycoumarin revealed an even stronger induction of EROD activity with maxima at about 10-32 microM, reaching BNF values. In contrast incubation with 7-benzyloxycoumarin had no evident inducing or suppressing effect, neither on EROD nor on PROD activity.

The kinetics of vitamin E was followed in serum, liver and kidney of 10- and 55-day-old rats after the administration of a single i.m. dose of 100 mg alpha-tocopherol acetate/100 g body wt. The basal levels without vitamin E administration were significantly higher in serum and liver of 10- than 55-day-old rats. The effect of vitamin E on cisplatin (CP; 0.6 mg/100 g body wt., i.p.) nephrotoxicity was investigated by determining urinary volume and protein excretion, as well as the concentration of blood urea nitrogen (BUN) and lipid peroxides in renal tissue (LPO). Previously described age differences in CP nephrotoxicity were confirmed. The administration of vitamin E, 12 h prior to CP, diminished the toxic effect of CP in young and adult rats. This effect could not be enhanced by a second administration of vitamin E. The simultaneous administration of vitamin E and C 12 h prior to CP intensified the protective effect of a single administration of vitamin E in 10- and 55-day-old rats without influencing the concentration of platinum in renal tissue.

In vitro influence of sodium selenite on cytochrome P-450-dependent formation of active oxygen species on lipid peroxidation (LPO) in rat liver microsomes was studied. Sodium selenite (10(-6)-10(-3) M) did not influence rates of NADPH/Fe-induced formation of active oxygen species (O2.-, OH., H2O2) and NAPDH-dependent LPO. Only at 10(-3) M selenite caused significant decrease in production of hydrogen peroxide in microsomes. Data obtained suggest that sodium selenite at physiological concentrations does not influence formation of active oxygen species by cytochrome P-450 and the rate of enzymatic LPO in rat liver microsomes.

P-450 dependent monooxygenation, which is responsible for detoxication and toxication of many xenobiotics, can be induced by many substances. Depending on the inducer, different P-450 forms are induced, which differ in their substrate specificity and in their involvement in the formation of toxic and carcinogenic metabolites. Therefore in toxicological investigations a sensitive and specific detection of the extent and type of induction is important. A simple detection is possible by measuring the metabolism of model substrates, e.g. ethylresorufin O-deethylation depends specifically on P-450 forms induced by, β-NF and other polycyclic aromatic hydrocarbons (Guengerich et al 1982), whereas pentylresorufin O-depentylation is considerably, but not specifically, induced by PB (Lubet et al 1985). Among 7-alkoxycoumarin derivatives 7-ethoxycoumarin was mostly used as a model substrate; its deethylation is induced by, β-NF and PB (Guengerich et al 1982). The aim of this study was to find 7-alkoxycoumarins and 7-alkoxy-4-methylcoumarins whose 7-dealkylation depends more specifically on certain P-450 forms.

Caffeine is mainly metabolized by 3-methylcholanthreneinducible cytochrome P-450, whereas metamizol (Analgin(R)) is probably mainly [metabolized by the phenobarbital inducible cytochrome P-450 family. Therefore the elimination of caffeine from serum and the elimination of the main metabolites of metamizol in urine reflect the activity of these two cytochrome P-450 families. Sex hormones can influence the activity of cytochrome P-450. Intake of levonorgestrel (0. 125 mg) daily for 14 days reduced the metabolism of caffeine slightly, but the elimination of metamizol-metabolites is not influenced. Longterm administration of levonorgestrel (0.250 mg daily) for three months did not change the metabolisms of both model substances tested. In contrast, ethynylestradiol (0.050 mg) alone and also the combination with levonorgestrel markedly retarded the elimination rate of caffeine and metamizol-metabolites. This fact should be taken into consideration in drug therapy.

Caffeine is mainly metabolized by 3-methylcholanthreneinducible cytochrome P-450, whereas metamizol (Analgin) is probably mainly metabolized by the phenobarbital inducible cytochrome P-450 family. Therefore the elimination of caffeine from serum and the elimination of the main metabolites of metamizol in urine reflect the activity of these two cytochrome P-450 families. Sex hormones can influence the activity of cytochrome P-450. Intake of levonorgestrel (0.125 mg) daily for 14 days reduced the metabolism of caffeine slightly, but the elimination of metamizol-metabolites is not influenced. Longterm administration of levonorgestrel (0.250 mg daily) for three months did not change the metabolisms of both model substances tested. In contrast, ethynylestradiol (0.050 mg) alone and also the combination with levonorgestrel markedly retarded the elimination rate of caffeine and metamizol-metabolites. This fact should be taken into consideration in drug therapy.

"Essential" phospholipids (EPL; polyene-phosphatidylcholine) were administered orally to aging male rats in doses of 100 and 300 mg/kg b.wt. over 10 weeks. One and 7 days after the last treatment cytochrome P-450 concentration, epoxide hydrolase and glutathione-S-transferases were found to be unchanged, but ethylmorphine N-demethylation, ethoxycoumarin O-deethylation and UDP-glucuronosyltransferase activities were enhanced, as were the concentrations of both reduced and oxidized glutathione, the values being similar to those in young adult rats. These results are discussed in terms of an increase in endoplasmic reticulum membrane fluidity.

The influence of metenolone acetate (1 mg/kg b.m. orally) on intact and chronically thioacetamide-injured rat liver (experimental liver cirrhosis) was investigated over 14 d. Histological examination revealed nodular transformation of liver structure according to cirrhosis like lesions with hepatocellular and cholangiocellular proliferations. These structural alterations were more serious in the group treated with metenolone compared with the group without metenolone. Metanolone administration to animals with thioacetamide-induced experimental liver cirrhosis led to an increase in liver injury. This treatment seems to promote hepatic preneoplastic lesions induced by thioacetamide reflected by histology and induction of gamma-glutamyltranspeptidase and 7-ethoxycoumarin O-deethylase in injured livers. Metenolone did not interfere directly with the processes of connective tissue synthesis and degradation after thioacetamide pretreatment. Only little changes of the investigated biochemical parameters were seen after metenolone administration to animals with intact liver function: increases in serum cholinesterase and tissue N-acetyl-beta-D-glucosaminidase activity; decreases in N-acetyl-beta-D-glucosaminidase in serum, liver hydroxyproline content and hepatic gamma-glutamyltranspeptidase activity. The observed changes reflect hepatic adaption processes under the influence of metenolone. The results of this study indicate that the risk of anabolic steroids in adjuvant therapy of liver cirrhosis cannot be calculated at present.

Caffeine is mainly metabolized by 3-methylcholanthreneinducible cytochrome P-450 whereas metamizol (Analgin) is probably metabolized mainly by the phenobarbital inducible cytochrome P-450 family. Therefore the elimination of caffeine from serum and the elimination of the main metabolites of metamizol in urine reflect the activity of these 2 cytochrome P-450. Intake of 0.125 mg levonorgestrel daily for 14 days reduced the metabolism of caffeine slightly but the elimination of metamizol-metabolites is not influenced. Longterm administration of levonorgestrel 0.250 mg daily for 3 months did not change the metabolisms of both model substances tested. In contrast ethinyl estradiol 0.050 mg alone and the combination with levonorgestrel markedly retarded the elimination rate of caffeine and metamizol-metabolites. This fact should be taken into consideration in administering drug therapy. (authors modified) (summaries in GER ENG)

The elimination of caffeine from serum and that of the main metabolites of metamizol in serum were investigated in 9 healthy women on days 1, 8, 14 and 21 of the menstrual cycle. In the luteal phase, when the progesterone level is highest and the estradiol concentration is high as well, the elimination of caffeine is about 25% longer than in the follicular phase. In contrast to caffeine, the metabolism of metamizol is slightly accelerated if the endogenous hormone level is high. The present results suggest that endogenous hormones have different effects on biotransformation activities. These results are without practical consequences yet.