CYP hepatic

Major CYP enzymes responsible for metabolizing various drugs 

Legend Major enzyme/s responsible for the hepatic metabolism of the specific substrate (e.g. drug) 

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There are several examples of autoimmune hepatitis caused by mechanism-based inhibitors in the field of CYPs hepatitis induced by halothane (CYP2E1) [15,16], by tienilic acid (CYP2C9) [17] and by dihydralazine (CYP1A2) [18,19]. 

The main cytochrome P450 (CYP) hepatic enzymes responsible for metabolizing antidepressant drugs... 

In Sprague-Dawley rats, the mRNA transcript for hepatic CYPlAl, IBl, and 2B1/2 and mammary CyplAl were up-regulated after treatment with indole-3-carbinol at 250 mg/kg (Horn et al. 2002). However, the level of expression of CYPIBI in the liver was lower than that of other CYPs. Hepatic P450 probe activities indicative of induction of CYPlAl, 1A2, and 2B1/2 were increased by indole-3-carbinol in a dose-dependent marmer. Treatment with... 

Nuclear Receptor Regulation of Hepatic Cytochrome P450 Enzymes. Figure 1 General mechanism for transcriptional activation of CYP genes by xenochemicals that activate their cognate xeno-receptor proteins. In the case of Ah receptor, the receptor s heterodimerization partner is Arnt, whereas in the case of the nuclear receptors CAR, PXR, and PPARa, the heterodimerization partner is RXR. The coactivator and basal transcription factor complexes shown are each comprised of a large number of protein components. 

Barber, D.S., McNally, A.J., Denslow, N.D., and Garcia-Reyero, N. et al. (2007). Exposure to p,p -YyOE or dieldrin during the reproductive season alters hepatic CYP expression in largemouth bass (Micropterus salmoides). Aquatic Toxicology 81, 27-35. 

Rifampin Hepatic abnormalities monitor LFTs Reddish-orange discoloration of secretions (e.g., urine, sweat, tears) Potent inducer of CYP-mediated metabolism evaluate for drug-drug interactions... 

Rescriptor tabs mg tabs can be dispersed in greater than or equal to 3 oz of water to produce slurry) 200 mg tabs should be administered whole separate dosing from buffered DDI or antacids by 1 hour with hepatic impairment LFTs, headaches cytochrome P-450 (CYP) CYP3A inhibitor 51% excreted in urine (less than 5% unchanged) 44% in feces... 

In addition to the mechanistic simulation of absorptive and secretive saturable carrier-mediated transport, we have developed a model of saturable metabolism for the gut and liver that simulates nonlinear responses in drug bioavailability and pharmacokinetics [19]. Hepatic extraction is modeled using a modified venous equilibrium model that is applicable under transient and nonlinear conditions. For drugs undergoing gut metabolism by the same enzymes responsible for liver metabolism (e.g., CYPs 3A4 and 2D6), gut metabolism kinetic parameters are scaled from liver metabolism parameters by scaling Vmax by the ratios of the amounts of metabolizing enzymes in each of the intestinal enterocyte compart-... 

HU, a freely water-soluble molecule, crosses the intestinal wall and other cells by passive diffusion [5, 6], and tissue concentration of HU rapidly matches its blood concentration [7]. The oral bioavailability of HU is nearly complete and hence therapeutically simple to administrate. HU undergoes biotransformation and is converted into urea by a yet-to-be identified hepatic P450 monooxygenase (CYP) enzyme [8, 9], Elimination of HU and its metabolites involves both renal and non-renal mechanisms. 

Tienilic acid- and dihydralazine-induced hepatitis are associated with antibodies against Cyp 2C9 [53] and Cyp 1A2 [54, 55], respectively. These are also the same cytochrome P450s that are responsible for the formation of reactive metabolites of these two drags. Anticonvulsant hepatotoxicity is associated with antibodies against rodent Cyp 3 A and related human enzymes such as thromboxane synthase [56, 57], It is interesting to note that cytochromes P450 are often the target of autoantibodies in idiopathic autoimmune hepatitis [58],... 

Minocycline is associated with a relatively high incidence of hepatotoxicity. In many cases it is quite distinct from minocycline-induced lupus, occurs earlier in the course of treatment (about 1 month), and the mechanism is unknown [62], However, in some cases the liver toxicity merges with the lupus-like syndrome, occurring after about a year of therapy, and is associated with ANA. This form is indistinguishable from idiopathic autoimmune hepatitis [63], and antibodies against Cyp 3A6 and Cyp 2C4 have been reported [64], Diclofenac has also been reported to cause hepatitis with autoimmune features such as ANA [65],... 

A rare but serious event that can result from irreversible CYP inhibition is the development of a hypersensitivity reaction. The bioactivation of a drug and the formation of a covalent adduct between the activated substrate and the enzyme can lead to hapten formation and eventually to an idiosyncratic autoimmune response (usually in the form of autoimmune hepatitis) [14]. The hapten formation is the first key step toward the autoimmune response. The CYP macromolecule is made immunogenic ( foreign ) by the covalent binding of the electrophilic metabolites, and the immune reaction follows with the production of autoantibodies against the target molecule (not necessarily alkylated). 

With the exception of two dehydrogenases, all of the steroidogenic enzymes belong to the cytochrome P-450 (abbreviated as CYP) family of enzymes. The CYP enzymes are often involved with redox or hydroxylation reactions, and are also found in the liver where they are key players in biotransformation reactions (see Section 6.4). Different members of the CYP family are therefore involved with both synthesis in adrenal and gonads and hepatic inactivation of steroid hormones. 

All tissues except mature red blood cells are able to manufacture haem for use in the respiratory cytochrome proteins of the electron transport chain. However, the liver is an especially important site of haem synthesis because it (a) is a major organ of erythropoiesis in utero and (b) haem-containing cytochrome-P450 (CYP-450) enzymes play significant roles in hepatic detoxification of drugs, toxins and endogenous waste products (Section 6.4). 

LC/MS/MS with selected reaction monitoring (SRM) offers a fast and simple means to analyze biological matrices, which is a key factor in high-throughput CYP inhibition screens using liver microsomes. Potentially, the LC/MS/MS technique is suitable for analyses of cocktail substrates in other in vitro drug metabolism evaluations such as CYP induction/activation assays, rapid analysis of pooled liver microsomes, rapid reaction phenotyping of tissue (hepatic and extrahepatic) samples, as well as evaluation of hepatocytes/tissue slice CYP activity. ° ... 

Kidney failure not only decreases renal clearance of nicotine and cotinine, but also metabolic clearance of nicotine (Molander et al. 2000). Metabolic clearance of nicotine is reduced by 50% in subjects with severe renal impairment compared to healthy subjects. It is speculated that accumulation of uremic toxins may inhibit CYP2A6 activity or downregulate CYP2A6 expression in liver. Hepatic metabolism of several drugs is reduced in kidney failure, mainly via downregulation of CYP enzymes and/or inhibition of transporters (Nolin et al. 2003). 

The main route of nicotine metabolism is through hepatic oxidation. In vitro, nicotine is oxidized by CYPs at the 5 carbon (C-oxidation) of the pyrrolidine ring. 

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