Microsomal monooxygenases

There is increasing evidence that microsomal monooxygenases with cytochrome P450 as their active center have a dominant role in the detoxication of the great... 

FIGURE 2.8 Monooxygenase activities of mammals, birds, and fish, (a) Mammals and birds, (b) Mammals, birds, and fish. Activities are of hepatic microsomal monooxygenases to a range of substrates expressed in relation to body weight. Each point represents one species (males and females are sometimes entered separately) (from Walker et al. 2000). 

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. 

In rats and mice, TBT compounds are hydroxylated by microsomal monooxygenase attack (see Environmental Health Criteria 116). Hydroxylation can occur on either the alpha or beta carbon of the butyl group, that is, alpha or beta in relation to the Sn atom (see Figure 8.5). After hydroxylation, the hydroxylated moiety breaks away to leave behind dibutyltin. 

The metabolism of permethrin will be taken more generally as an example of the metabolism of pyrethroids (Figure 12.2). The two types of primary metabolic attack are by microsomal monooxygenases and esterases. Monooxygenase attack involves... 

Cytochrome P450 A hemeprotein that catalyzes many biological oxidations (see also microsomal monooxygenases). 

Fent, K. and Bucheli, T.D. (1994). Inhibitors of hepatic microsomal monooxygenase system by organotins in vitro in freshwater fish. Aquatic Toxicology 28, 107-126. 

Walker, C.H. (1978). Species differences in microsomal monooxygenase activities and their relationship to biological half lives. Drug Metabolism Reviews 7(2), 295-323. 

Funari E, A Zoppinki, A Verdina, G de Angelis, L Vittozzi (1987) Xenobiotic metabolizing enzyme systems in test fish. I. Comparative studies of liver microsomal monooxygenases. Ecotoxicol Environ Saf 13 24-31. 

Forti, G.C., Paolini, M., Hrelia, P. et al. (1984) NADPH-generating system influence on microsomal monooxygenase stability during incubation for the liver microsomal assay with rat and mouse S9 fractions. Mutation Research, 129, 291-297. 

Vodicnik, M.J., C.R. Elcombe, and J.J. Lech. 1981. The effect of various types of inducing agents on hepatic microsomal monooxygenase activity in rainbow trout. Toxicol. Appl. Pharmacol. 59 364-374. 

Fingerlings were injected ip with 14C-labeled PCB mixture at 0.3,1,3,10, and 30 mg PCB/kg BW tissues sampled up to 70 days postinjection At 3 days postinjection high doses of 10 and 30 mg PCB/kg BW caused elevation of liver microsomal monooxygenase activity when maximum tissue concentrations, in mg total PCB/kg FW, were 55 in bile, 12 in blood, 8 in muscle, and 8 in liver. Elevated hepatic microsomal monooxygenase activity with muscle and liver PCB concentrations of >0.3 mg/kg FW, but not 0.25 mg/kg FW 6... 

Melancon, M.J., K.A. Tumquist, and J.J. Lech. 1989. Relation of hepatic microsomal monooxygenase activity to tissue PCBs in rainbow trout (Salmo gairdneri) injected with [14C] PCBs. Environ. Toxicol. Chem. 8 777-782. 

Oikari, A. and B. Jimenez. 1992. Effects of hepatotoxicants on the induction of microsomal monooxygenase activity in sunfish liver by beta-naphthoflavone and benzo[a]pyrene. Ecotoxicol. Environ. Safety 23 89-102. 

Also included in these in vivo studies were trials with the microsomal monooxygenase inhibitor, SKF 525-A. As in the cases of the susbtrates, no remarkable effects were observed. The fate of the inhibitor is unknown. To date, SKF 525-A exposures have not been coupled with measurements of oxidative metabolism. 

In an attempt to resolve these questions, we have directed studies toward examining the interaction of chemicals with the hepatic microsomal monooxygenase system of fish and to determine whether multiple forms of hemoprotein(s) P-450 exist, and, if so, how the relative microsomal hemoprotein subpopulations are altered by xen ob i oti cs. 

Phenol is catabolized by liver microsomal monooxygenases to hydroxylated products (e.g., 1,4-dihydroxybenzene) that can undergo further conversion to a variety of electrophilic substances (e.g., benzoquinones). Such reactions may be involved in generating reactive toxic intermediates in the liver (Eastmond et al. 1986 Lunte and Kissinger 1983 Subrahmanyam and O Brien 1985). Based on the available data, hepatic effects are unlikely to occur at the exposure levels found in the environment or near hazardous waste sites. 

Dibromoethane is metabolized to active forms capable of inducing toxic effects by either of two systems-the microsomal monooxygenase system (cytochrome P-450 oxidation) and the cytosolic activation system (glutathione conjugation). Figure 2-3 provides an overview of the metabolism of... 

Once absorbed, 1,2-dibromoethane is rapidly metabolized. Its metabolism may induce effects by either of two systems, the microsomal monooxygenase system or the cytosolic activation system. Animal research has shown that seventy percent of 1,2-dibromoethane is excreted in the urine and feces within 48 hours. The lack of persistent metabolites in the tissues indicate that... 

Cytochrome P450, subfamily lie (mepheny-toin 4-hydroxylase), polypeptide 19 flavo-protein-hnked monooxygenase mephenytoin 4 -hydroxylase microsomal monooxygenase xenobiotic monooxygenase... 

Starek A. 1988. [The effect of kerosene hydrocarbons on microsomal monooxygenases activity in rat liver.] Folia Med Cracov 29(3-4) 161-170. (Polish)... 

Short CL, Kinden DA, Stith R. 1976. Fetal and neonatal development of the microsomal monooxygenase system. Drug Metab Rev 5 1-42. 

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