Liver cytochrome P450 isoforms

Prakash, C., Kamel, A., Cui, D., Whalen, R.D., Miceli, J.J., and Tweedie, D. (2000) Identification of the major human liver cytochrome P450 isoform(s) responsible for the formation of zi-prasidone and prediction of possible drug interactions. Br Clin Pharmacol 49 35S-42S. 

Andersson T, Miners JO, Veronese ME, et al. Identification of human liver cytochrome P450 isoforms mediating omeprazole metabolism. Br J Clin Pharmacol 1993 36 521-530. 

Shin, J.G., Soukhova, N., and Flockhart, D.A. (1999) Effect of antipsychotic drugs on human liver cytochrome P450 (CYP) isoforms in vitro preferential inhibition of CYP2D6. Drug Metab Dfspos 27 1078-1084. 

LED, lowest effective dose HID, highest ineffective dose in-vitro tests, ug/nil, in-vivo tests, mg/kg bw/day ip, intraperitoneal po, oral ° Cells pre-incubated for 24 h with 2 uM dexamethasone, an inducer of liver-specific cytochrome P450 isoforms results were negative without this pretreatment. 

Ames Test The Ames test, developed by Bruce Ames and his coworkers at the University of California, Berkeley, depends on the ability of mutagenic chemicals to bring about reverse mutations in Salmonella typhimurium strains that have defects in the histidine biosynthesis pathway. These strains will not grow in the absence of histidine but can be caused to mutate back to the wild type, which can synthesize histidine and hence can grow in its absence. The postmitochondrial supernatant (S-9 fraction), obtained from homogenates of livers of rats previously treated with PCBs in order to induce certain cytochrome P450 isoforms, is also included in order to provide the activating enzymes involved in the production of the potent electrophiles often involved in the toxicity of chemicals to animals. 

The widespread use of isoniazid prophylaxis for tuberculosis has focused attention on the liver injury caused by this drug. About 20% of patients treated with isoniazid will show elevated blood concentrations of liver enzymes and bilirubin that subside as treatment is continued (25). However/ clinical hepatitis develops in some patientS/ and these reactions can prove fatal. Current understanding of the mechanism of isoniazid-induced hepatotoxicity is based on the metabolic pathways shown in Figure 16.6 (26/ 27). It has been demonstrated in an animal model that hepatotoxicity is correlated with plasma concentrations of hydrazine but not of acetylhydrazine or isoniazid (28)/ and that pretreatment with an amidase inhibitor can prevent toxicity (27). However/ it is postulated that hydrazine is further metabolized to a chemically reactive he pa to toxin by the cytochrome P450 system/ and in vitro studies with hepatocytes have implicated CYP2E1 as the cytochrome P450 isoform responsible for cytotoxic metabolite formation (29). 

Rifkind, A.B., A. Kanetoshi, J. Orlinick, J.H. Capdevila, and C. Lee (1994). Purification and biochemical characterization of two major cytochrome P450 isoforms induced by 2,3,7,8-tetrachlorodibenzo-/ -dioxin in chick embryo liver. J. Biol. Chem. 269, 3387-3396. 

Buratti, F. M., D Aniello, A., Volpe. M. T Meneguz. A., and Testai, E. (2004 November 22), Malathion bioactivation in the human liver The contribution of different cytochrome P450 isoforms. Drug Metab. Disp., online publication. 

Obach RS. Metabolism of ezlopitant, a nonpeptidic substance P receptor antagonist, in liver microsomes enzyme kinetics, cytochrome P450 isoform identity, and in vitro-in vivo correlation. Drug Metab Dispos 2000 28 1069 1076. 

Kim K-A Pari J-Y. Inhibitory effect of glyburide on human cytochrome P450 isoforms in human liver microsomes. DrugMetab Dispos (2003) 3,1090-2. 

Kawakami H, Ohtsuki S, Kamiie J, Suzuki T, Abe T, Terasaki T (2011) Simultaneous absolute quantification of 11 cytochrome P450 isoforms in human liver microsomes by liquid chromatography tandem mass spectrometry with in silico target peptide selection. J Pharm Sci 100 341-352... 

HaniokaN, Jinno H,NishimuraT, Ando M (1998) Suppression of male-specific cytochrome P450 isoforms by bisphenol A in rat liver. Arch Toxicol 72 387-394... 

Choi and Soderlund (2006) identified human alcohol (ADH) and aldehyde dehydrogenases (ALDH) as the enzymes involved in the oxidation of PB alcohol (phenoxybenzyl alcohol) from trans-permethrin to PB acid (phenoxybenzoic acid) via phenoxybenzaldehyde. C -Permethrin was not metabolized to any extent in human liver fractions. Cytochrome P450 isoforms were not involved either in the hydrolysis of traws-permethrin or in the oxidation of the PB alcohol to the PB acid. 

Makaji, E. Trambitas, C. S. Shen, P. Holloway, A. C. Crankshaw, D. J. Effects of cytochrome P450 inhibitors on the biotransformation of fluorogenic substrates by adult male rat liver microsomes and cDNA-expressed rat cytochrome P450 isoforms. Toxicol. Set 2010,113, 293-304. 

Cytochrome P450 (EC 1.14.14.1) enzymes are well known for their ability to metabolize the majority of drugs, to detoxify environmental pollutants, and to activate some classes of carcinogens [93]. The most highly expressed subfamily is CYP 3A, which includes the isoforms CYP 3A4, CYP 3A5, CYP 3A7, and CYP 3A43 [93, 94]. The most abundant isoform is CYP 3A4, which corresponds to 30% of the total P450 content in the liver and about 70% of the total P450 content in the... 

Metabolism - In vitro studies in human liver microsomes indicate that ertapenem does not inhibit metabolism mediated by any of the following cytochrome P450 (CYP) isoforms 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4. 

Yang LQ, Li SJ, Cao YF, et al. Different alterations of cytochrome P450 3A4 isoform and its gene expression in livers of patients with chronic liver disease. World J Gastroenterol. 2003 9 359-363. 

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