Role of cytochrome P-450 and related enzymes in the pulmonary metabolism of xenobiotics.

Abstract

The lung metabolizes a wide variety of xenobiotics and, in the process, forms products that may be more or less toxic than the parent compound. The consequence of metabolism, activation or detoxication, is a function of the nature of the substrate and of the characteristics and concentrations of the enzymes involved. As a result, the biotransformation of xenobiotics can lead to their excretion or to the formation of reactive products that produce deleterious effects by binding covalently to tissue macromolecules. Among the enzymes that metabolize xenobiotics, those associated with the cytochrome P-450-dependent monooxygenase system are probably the most important. The route by which a given substrate is metabolized in a tissue or cell is, to a great extent, determined by the types and concentrations of cytochrome P-450 isozymes present. We are just beginning to understand the distribution of these enzymes in lung and to appreciate the species and cellular differences that exist.

LOW-LEVEL m-XYLENE INHALATION ALTERS PULMONARY AND HEPATIC CYTOCHROME P-450 ACTIVITY IN THE RAT

“…A significant decrease in CYP 4B1 activity in lung was observed after exposure to m-xylene vapor ( Figure 2B). This isozyme is partially responsible for the metabolism of xylenes in the lung (Philpot & Smith, 1984) and is also responsible for the metabolism of arom atic amines to reactive metabolites that have been linked to bladder cancer (Beland et al, 1983). A decrease in activity would result in decreased metabolism of aminofluorene with a resulting decrease in reactive metabolite formation.…”

Cytochrome P4502A‐Mediated Cownarin 7‐Hydroxylation and Testosterone Hydroxylation in Mouse and Rat Lung

“…Although liver is the predominant organ for the metabolism of foreign chemicals, the lungs display quite a diversified array of drug-metabolizing activities, including cytochrome P450-associated oxidative reactions (Philpot & Smith 1984). Individual isoforms belonging to the P450 families 1 through 4 have been either purified or characterized by indirect methods in the rabbit, hamster and rat lung (Guengerich 1990).…”

Oxygen Metabolism in the Lung

“…The lung can metabolize a number of drugs, including phenobarbital, methadone, lidocaine, and several steroids (Devereux et al, 1989;Philpot and Smith, 1984;Blase and Loomis, 1976;Hartiala, 1976;Post et al, 1978;Nicholas and Kim, 1975), and much of this metabolism occurs in both Clara and type II epithelial cells (Devereux et al, 1981). The lung is one of the major sites for cytochrome-P450 activity outside of the liver (Gasser et al, 1988;Lawton et al, 1990).…”

“…Lung cytochrome-P450 monooxygenase activity is approximately one-twentieth to one-tenth (per unit weight) that of the liver. Also, compared with the liver, the lung shows a relatively small inducibility for cytochrome-P450 monooxygenase activity with drug substrates such as phenobarbital (Philpot and Smith, 1984). Nevertheless, aryl hydrocarbon hydroxylase activity can be induced up to 15-fold in rat lung by treatment with 3-methylcholanthrene (Matsubara et al, 1974) and its induction is associated with exposure-related mitochondrial dysfunction (Bansal et al, 2014).…”

“…The inducible aryl hydrocarbon hydroxylase activity of the lung may be particularly important in the formation of carcinogens from cigarette smoke components, and polymorphisms in these enzymes may be a risk factor for the development of lung cancer (Hussain et al, 2014;Hussein et al, 2014;Kim et al, 2004). The lung-specific activity for metabolism of some inhaled agents, particularly benzene and pxylene, exceeds the activity in the liver (Philpot and Smith, 1984) and is critical to the bioactivation of a range of pulmonary toxicants (Kartha and Yost, 2008).…”