实验动物 z-bo 2020-12-30 603

　　Introduction: As long as different enzymes are decisively involved in the metabolism of the compound under consideration, choosing the appropriate system will be different. Since the different properties of the compound may depend on the degree of removal of different metabolites or parent compounds, different systems may be needed to study different properties, even for a given compound. The lung of a mammal is a very complex organ with many compartments and more than 40 different cell types. From the data collected in this article, we can see that the patterns of exogenous metabolic enzymes in these different cell compartments and cell types are different. Most of the information currently available to identify the relative suitability of individual experimental animal species or human in vitro models in simulating human lung conditions comes from whole organ lungs, such as lung homogenate and partial lungs. The changes in the levels and/or activities of these enzymes during carcinogenesis and in cancer cells as well as polymorphisms and their effects on cancer susceptibility have been excluded from this review and may become the subject of future reviews. (1) Some lung heterogeneous metabolic enzymes such as cytochrome P450 (CYPs) have very low activity, so it is difficult to accurately measure. (2) Many of the activities cited in this review and/or table are derived from original publications, which do not state whether a given rate has been properly tested under certain linear conditions. Therefore, not all values presented are comparable. Therefore, it is wise to treat the values quoted in this review as representing only high, medium, low, or unobserved activities. Similar considerations apply to low activity and inactivity, because in most "zero activity" cases, the detection limit is not given by the author, and the low activity number given by one author may actually be lower than that given by another author. Zero activity out. Each exogenous metabolic enzyme family/superfamily will be briefly introduced when it first appears.

　　Exogenous metabolic enzymes in rat lung: Cytochrome P450: Cytochrome P450 is the main exogenous metabolic oxidoreductase in mammalian liver and some extrahepatic tissues. CYP reductase: Zhu et al. (1985) found CYP4A mRNA in rat pulmonary artery endothelial cells and smooth muscle cells, bronchial epithelial cells and smooth muscle cells, type I epithelial cells and macrophages. Hellmold (1993) et al. reported the expression of CYP4A2 and CYP 4A8 in rat lungs. Zeldin et al. (1996) found CYP2J3 mRNA in rat lungs. Lake et al. (2003) induced CYP1A1 mRNA (up to 8.3 times) by exposure to BNF (β-naphthol flavone), aroclor 1254 or BP in precisely cut rat lung slices. Gate et al. (2006) reported that CYP1A1 and 1B1 in rat lungs were significantly increased (26-2203 times), and CYP2F2 mRNA levels were significantly reduced (2.4 times) after rats were exposed to asphalt smoke.

　　 non-CYP oxidoreductase "Flavin-dependent monooxygenase (FMO): FMO occurs in the liver of mammals and appears to be an important xenogeneic metabolic oxidoreductase in extrahepatic tissues, the latter may be more important than CYP. However, their substrate specificity is limited to soft nucleophilic centers, most notably the conversion of nitrogen and sulfur atoms in xenobiotic molecules into N-oxide and S-oxide. Sukumaran (2011) et al. reported the presence of FMO2 and FMO3 mRNA and their circadian changes in rat lungs.

　　NAD(P)H: Quinone oxidoreductase (NQO): NQO avoids semiquinone free radicals as the main metabolite by direct 2-electron reduction, thereby preventing quinone toxicity. NQO converts carbonyl functional groups into hydroxyl functional groups, and is generally used as a substrate for glucuronyltransferase and/or sulfotransferase binding, and then promotes excretion. NADH or NADPH can be used as the reducing equivalent. Gate (2006) and others reported a significant increase (6.7-fold) of NQO1 mRNA in the lungs of rats exposed to asphalt smoke.

　　 Alcohol dehydrogenase (ADH): ADHs convert alcohols into aldehydes or ketones. Ethanol is converted to acetaldehyde by ADH, which is mainly responsible for the acute toxicity of ethanol. NAD is used as an electron acceptor. Aldehyde dehydrogenase (ALDH): ALDH converts aldehydes into corresponding carboxylic acids. This step usually represents detoxification. Aldehyde oxidase (AO): AO catalyzes the conversion of aldehydes to carboxylic acids by simultaneously forming hydrogen peroxide. It uses molecular oxygen as an electron acceptor.

　　 binding enzyme

　　 Glutathione S-transferase (GST): GST converts electrophilic foreign compounds into their glutathione (GSH) conjugates. This is usually detoxifying, but in some cases it is toxic. Glucosyltransferase: UGTs convert exogenous compounds with appropriate substituents (mainly hydroxyl, sometimes amino, sulfhydryl or carboxyl) into glucuronate. This is usually detoxification, but in some cases (such as "acyl migration") it can cause toxicity.

　　Exogenous metabolic enzyme in rabbit lung: Cytochrome P450: The expression of CYP4B1 mRNA in rabbit lung tissue is significantly higher than that in liver and other tissues. Expression of CYP and its related proteins: Serabjit Singh et al. (1980) observed CYP reductase protein in rabbit lung Clara (Club) cells. The localization of CYP reductase in rabbit lung Clara cells is higher than that in type II alveolar macrophages. There was no expression of CYP reductase protein in rabbit type I lung cells and endothelial cells. CYP1A1 and CYP1A2 proteins were not detected in rabbit lung tissues, but in bronchus, bronchiolar epithelium, pulmonary artery, vein and capillary endothelial cells, TCDD can induce the expression of CYP1A1 and CYP1A2 proteins. The content of CYP1A1 in rabbit alveolar macrophages is low. CYP2B4 was observed in rabbit Clara cells and type I lung cells, bronchial and bronchiolar epithelium and even type I lung cells. The relative content of CYP2B4 is higher in Clara cells, while the relative content of CYP2B4 is lower in ciliated epithelial cells of bronchus and bronchioles. CYP4B1 has the highest content in Clara cells, bronchial ciliated cells and bronchiociliated cells, type II lung cells and capillary endothelial cells, but not in type II lung cells. Non-CYP oxidoreductase: Flavin-dependent monooxygenase (FMO), aldehyde ketone reductase (AKR). Hydrolase: Epoxyhydrolase (EH): Microsomal epoxyhydrolase (mEH, also known as EPHX1), soluble epoxyhydrolase (sEH, also known as EPHX2). Exogenous metabolic enzymes in golden hamster lungs: Cytochrome P450 (CYP): Lorenz et al. (1984) demonstrated that golden hamster lung microsomes effectively catalyze the desorption of the broad-spectrum CYP substrate 7-ethoxycoumarin Ethyl is about 5 times slower than mouse lung microsomes, similar to rat lung microsomes, but more than 100 times faster than human lung microsomes. Golden hamster lung Clara (Club) cells have long been identified as the main location for CYP-dependent covalent binding. Paolini et al. (1995) reported the CYP2B-dependent PROD activity in the lungs of golden hamsters and the induction effects of several compounds (phenobarbital sodium, barbital sodium, cyclophosphamide) on it. Binding enzymes: glutathione S-transferase (GST), sulfotransferase (SULT). Exogenous metabolic enzymes in guinea pig lungs: Cytochrome P450 (CYP): Bilimoria et al. (1977) observed total homogenized AHH activity in guinea pig lungs. After the animals were exposed to cigarette smoke, the AHH activity was significantly reduced (about 50%). %).

　　Exogenous metabolic enzymes in pig lung: Cytochrome P450 (CYP): CYP1A1 and CYP1A2 transcripts are observed in pig lung. The constitutive expression level of porcine CYP2B22 (homologous to human CYP2B6, 81% nucleotide homology) mRNA in pig lung is higher than that in liver. CYP2D25 (homologous to human CYP2D6, 83% nucleotide homology) is expressed at low levels in pig lungs. There are CYP3A22, 3A29 and 3A46 mRNA in pig lung tissue, but their expression level is much lower than that of liver. Binding enzyme: glutathione S-transferase (GST).

　　Exogenous metabolic enzymes in dog lung: Cytochrome P450 (CYP): Visser et al. (2017) observed the expression of CYP2B11 transcripts and the lowest expression of mRNAs of other exogenous metabolic enzymes in dog lung. CYP-catalyzed monooxygenation reactions of several exogenous compounds have been observed in dog lungs. Hydrolase: Epoxyhydrolase (EH). Binding enzyme: glutathione S-transferase (GST). Exogenous metabolic enzymes in monkey lungs: Marmoset: Cytochrome P450 (CYP): Uehara et al. (2018) observed highly expressed CYP2F1 transcripts in marmoset lungs, much higher than any other organs studied (liver, kidney , Jejunum, brain). By immunoblotting, it was found that the CYP2F1 protein in the marmoset lungs cross-reacted with the human CYP2F1 antibody. In marmoset lung microsomes, they observed the catalytic activity of several prototype CYP substrates, including coumarin, 7-ethoxycoumarin, and 2-/4-biphenyl, but not chlorzoxazone.

　　 Cynomolgus monkey: Cytochrome P450 (CYP): Uehara et al. (2018) confirmed the high expression of CYP2F1 transcript in cynomolgus monkey lung. In the cynomolgus monkey lung microsomes, they observed the catalytic activity of several typical CYP substrates, including coumarin, 7-ethoxycoumarin, 2-/4-biphenyl, but not chlorzoxa Zong.