Cytochrome P450, hepatic microsomal

The hepatic metabolism of all three phosphodiesterase inhibitors can be inhibited by cytochrome P450 hepatic microsomal enzyme... 

In addition to cytochrome P450s, hepatic microsomes contain another class of mono-oxygenases, the flavin-containing mono-oxygenases (FMO). These enzymes catalyse oxidation at nucleophilic nitrogen, sulfur and phosphorus atoms rather than oxidation at carbon atoms, e.g. for phenothiazines, ephedrine, norcocaine and the mono-ether and carbamate-containing pesticides. 

All three phosphodiesterase inhibitors are hepatically catabo-lized by the cytochrome P450 3A4 microsomal isoenzyme as well as by other P450 isoenzymes (minor routes) and/or other hepatic enzymes. The drugs and their metabolites (some of which are active) are excreted primarily in the feces, but also in the urine to varying degrees (see Table 84-4). 

Two important examples of reductive metabolism of xenobiotics are the reductive dehalogenation of organohalogen compounds, and the reduction of nitroaromatic compounds. Examples of each are shown in Figure 2.13. Both types of reaction can take place in hepatic microsomal preparations at low oxygen tensions. Cytochrome P450 can catalyze both types of reduction. If a substrate is bound to P450 in the... 

Under anaerobic conditions, p,p -DDT is converted to p,p -DDD by reductive dechlorination, a biotransfonnation that occurs postmortem in vertebrate tissues such as liver and muscle and in certain anaerobic microorganisms (Walker and Jefferies 1978). Reductive dechlorination is carried out by reduced iron porphyrins. It is carried out by cytochrome P450 of vertebrate liver microsomes when supplied with NADPH in the absence of oxygen (Walker 1969 Walker and Jefferies 1978). Reductive dechlorination by hepatic microsomal cytochrome P450 can account for the relatively rapid conversion of p,p -DDT to p,p -DDD in avian liver immediately after death, and mirrors the reductive dechlorination of other organochlorine substrates (e.g., CCI4 and halothane) under anaerobic conditions. It is uncertain to what extent, if at all, the reductive dechlorination of DDT occurs in vivo in vertebrates (Walker 1974). 

Scollon EJ, Starr JM, Godin SJ, DeVito MJ, Hughers MF (2009) In vitro metabolism of pyrethroid pesticides by rats and human hepatic microsomes and cytochrome p450 isoforms. Dmg Metab Dispos 37 221-228... 

Harris, J.W., Rahman, A., Kim, B.R., Guengerich, F.P. and Collins, J.M. (1994) Metabolism of taxol by human hepatic microsomes and liver slices participation of cytochrome P450 3A4 and an unknown P450 enzyme. Cancer Research, 54 (15), 4026-4035. 

Dihaloelimination is a two-electron transfer reaction. Thompson et al. [377] reported reductive dichloroelimination of 1,1,2-TCA and TeCA by hepatic micro-somes from rat Ever, with VC and both tDCE and cDCE as metabolites. Reductive dichloroelimination from hexa- and pentachloroethane by microsomal cytochrome P450 was studied by Nastainczyk et al. [378]. The main products of the in vitro metabolism of hexa- and pentachloroethane were PCE (99.5%) and TCE (96%), respectively, with minor amounts of pentachloroethane (0.5%) and TeCA (4%), respectively, via reductive dechlorination. 

An important drug in the present context is the mineralocorticoid receptor antagonist spironolactone (7.74, Fig. 7.12). Among its many metabolic reactions, spironolactone is readily hydrolyzed at the thioester bond (Fig. 7.12, Reaction a) to form deacetyl-spironolactone (7.75, Fig. 7.12), a metabolite found in a variety of tissues [155 -157]. This thiol compound, which is also a potent mineralocorticoid antagonist, promotes the mechanism-based inactivation of hepatic, adrenal, and testicular cytochrome P450 isozymes. There is now good evidence to indicate that this behavior is the result of microsomal 5-oxidation (see Chapt. 7 in [7]). When spironolactone was incubated with liver microsomes from rats pretreated with dexamethasone (an inducer of CYP3A), the sulfinic and sulfonic acid derivatives were characterized [158]. Perhaps the importance of the 5-deacetylation of spironolactone... 

Ohmori S, Horie T, Guengerich FP, Kiuchi M, Kitada M (1993b) Purification and characterization of two forms of hepatic microsomal cytochrome P450 from untreated cynomolgus monkeys. Arch Biochem Biophys 305 405 13... 

CYP1A2, and it also has been shown to be an inducer of CYP1A2 in rodents on account of the increase in hepatic microsomal CYP1A2. Rutaecarpine is an inducer of cytochrome P450(CYP)1A in mouse liver and kidney ". ... 

There is heterogeneity in human populations for the hepatic microsomal cytochrome P450 enzyme (see Chapter 4). Possession of an unfavorable phenotype may place a patient at risk for drug toxicity. For exam-... 

Young male Wistar rats were given 2000 mg/kg bw di(2-ethylhexyl) phthalate per day by gavage for periods of 3-21 days (Lake et al, 1975). Treatment caused increases in relative liver weight and in microsomal cytochrome P450 content. Ultra-structural examination revealed marked peroxisome proliferation and a dilation of the smooth and rough endoplasmic reticulum. Rats were also treated with mono(2-ethyl-hexyl) phthalate, 2-ethylhexanol and phthalic acid at doses equimolar to 2000 mg/kg bw per day di(2-ethylhexyl) phthalate for seven days. While phthalic acid had no effect, both mono(2-ethylhexyl) phthalate and 2-ethylhexanol increased relative liver weight and produced hepatic peroxisome proliferation. 

CYP2A6 (cytochrome P450 2A6) has been purified from human liver and CYP2A6 cDNA expression systems are available. Many studies have demonstrated marked interindividual variation in the levels of hepatic CYP2A6 protein, mRNA and associated microsomal coumarin 7-hydroxylase activity (reviewed in Pelkonen et al., 1997 Lake, 1999). The role of CYP2A6 in the metabolism of coumarin by human liver microsomes has been confirmed by Sai et al. (1999), who found that a monoclonal antibody to CYP2A6 inhibited coumarin 7-hydroxylation by more than 94%. 

In one-, four- and 13-week studies, the effects of coumarin treatment were compared in male Sprague-Dawley rats, CD-I mice and Syrian hamsters. Rats were fed 0-0.75% coumarin for one and four weeks and 0.5% coumarin for 13 weeks. Mice and hamsters were fed 0-0.5 and 0-1.0% coumarin, respectively, for one, four or 13 weeks. In the rat, coumarin caused dose-related hepatotoxic effects which included vacuolar degeneration, apoptosis and bile duct proliferation and increases in serum bilirubin content and both serum and hepatic y-glutamyltranspeptidase activity. A sustained stimulation of hepatocyte replicative DNA synthesis was observed in rats treated for four and 13 weeks. Levels of total hepatic glutathione were increased approximately twofold, and there were statistically significant decreases in microsomal cytochrome P450 content and ethylmorphine 7V-demethylase activity. These effects were reduced or not observed in mice and hamsters (Lake Grasso, 1996). 

Evans, J.G, Appleby, E.C., Lake, B.G Coiming, D M. (1989) Studies on the induction of cholangiofibrosis by coumarin in the rat. Toxicology, 55, 207-224 Faurschou, P. (1982) Toxic hepatitis due to benzo-pyrone. Hum. Toxicol, 1, 149-150 Fentem, J.H. Fry, J.R. (1991) Comparison of the effects of inducers of cytochrome P450 on Mongolian gerbil and rat hepatic microsomal monooxygenase activities. Xenobiotica, 21, 895-904... 

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