Cytochrome P450, xenobiotic-metabolizing

Yang CS, Brady JF, Hong JY Dietary effects on cytochromes P450, xenobiotic metabolism, and toxicity. FASEB J 1992 6 737. 

Bhagwat SV, Boyd MR, Ravindranath V. 1995a. Brain mitochondrial cytochromes P450 xenobiotic metabolism, presence of multiple forms and their selective inducibility. Arch Biochem Biophys 320 73-83. 

Korzekwa KR, Jones JP. Predicting the cytochrome P450 mediated metabolism of xenobiotics. 

Wheeler, C. W., T. M. Guenthner. Cytochrome P450-dependent metabolism of xenobiotics in human lung. J. Biochem. Toxicol. 6 163-169, 1991. 

During periods of immune system response, for example, at times of infectious disease, cytochrome P450-dependent metabolism of xenobiotics is reduced. This effect is attributed to the production of interferon by the immune system as it responds to a challenge. Human interferon has been shown to suppress the metabolism of benzo [a] pyrene in laboratory animalsJ19 ... 

Korzekwa, K.R. and Jones, J.P. (1993) Predicting the cytochrome P450 mediated metabolism of xenobiotics. Pharmacogenetics, 3 (1), 1-18. 

Cytochrome P450 Isoforms Metabolizing Drugs/Xenobiotics (18,19,20)... 

BSEP is a liver-specific and ATP-dependent transport protein that mediates the excretion of bile salts into bile and is expressed on the apical plasma membrane domain (canalicular surface) of hepatocytes (Lam et al., 2010). Bile formation and excretion is an essential biological process in higher vertebrates and is an important route of xenobiotic elimination, which also plays a key role in intestinal dissolution and absorption of lipids, vitamins, and fat-soluble food components. Bile salts are synthesized within hepatocytes by cytochrome P450-mediated metabolism of cholesterol and are key components of bile (Hofmann and Hagey, 2008). Bile formation and bile flow are regulated physiologically by complex mechanisms, which in hepatocytes include nuclear hormone receptor-mediated transcriptional pathways and a variety of posttranscriptional processes (Kullak-Ublick et al., 2004 Gonzalez, 2012). 

Xenobiotics metabolism, 1, 223-225 monooxygenation cytochrome P450 in, 1, 259-260 Xenon... 

The metabolism of foreign compounds (xenobiotics) often takes place in two consecutive reactions, classically referred to as phases one and two. Phase I is a functionalization of the lipophilic compound that can be used to attach a conjugate in Phase II. The conjugated product is usually sufficiently water-soluble to be excretable into the urine. The most important biotransformations of Phase I are aromatic and aliphatic hydroxylations catalyzed by cytochromes P450. Other Phase I enzymes are for example epoxide hydrolases or carboxylesterases. Typical Phase II enzymes are UDP-glucuronosyltrans-ferases, sulfotransferases, N-acetyltransferases and methyltransferases e.g. thiopurin S-methyltransferase. 

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... 

The microsomal fraction consists mainly of vesicles (microsomes) derived from the endoplasmic reticulum (smooth and rough). It contains cytochrome P450 and NADPH/cytochrome P450 reductase (collectively the microsomal monooxygenase system), carboxylesterases, A-esterases, epoxide hydrolases, glucuronyl transferases, and other enzymes that metabolize xenobiotics. The 105,000 g supernatant contains soluble enzymes such as glutathione-5-trans-ferases, sulfotransferases, and certain esterases. The 11,000 g supernatant contains all of the types of enzyme listed earlier. 

ISOFORMS OF CYTOCHROME P450 HYDROXYLATE A MYRIAD OF XENOBIOTICS IN PHASE 1 OF THEIR METABOLISM... 

Figure 53-1. Simplified scheme showing how metabolism of a xenobiotic can result in cell injury, immunologic damage, or cancer. In this instance, the conversion of the xenobiotic to a reactive metabolite is catalyzed by a cytochrome P450,and the conversion of the reactive metabolite (eg, an epoxide) to a nontoxic metabolite is catalyzed either by a GSH S-transferase or by epoxide hydrolase.

Xenobiotics are metabolized in two phases. The major reaction of phase 1 is hydroxylation catalyzed by a variety of monooxygenases, also known as the cytochrome P450s. In phase 2, the hydroxylated species are conjugated with a variety of hydrophihc compounds such as glucuronic acid, sulfate, or glutathione. The combined operation of these two phases renders lipophilic compounds into water-soluble compounds that can be ehminated from the body. 

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