Hepatic microsomal monooxygenases

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). 

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. 

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. 

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. 

Evans, J.G, Appleby, E.C., Lake, B.G Coiming, D M. (1989) Studies on the induction of cholangiofibrosis by coumarin in the rat. Toxicology, 55, 207-224 Faurschou, P. (1982) Toxic hepatitis due to benzo-pyrone. Hum. Toxicol, 1, 149-150 Fentem, J.H. Fry, J.R. (1991) Comparison of the effects of inducers of cytochrome P450 on Mongolian gerbil and rat hepatic microsomal monooxygenase activities. Xenobiotica, 21, 895-904... 

The ability of PBBs to induce hepatic Phase I xenobiotic metabolizing enzymes (cytochrome P-450-dependent monooxygenases) is well documented (Dannan et al. 1978b, 1982a, 1982b, 1983 Ecobichon et al. 1979 Moore et al. 1978, 1979 Parkinson et al. 1983 Robertson et al. 1982 Schramm et al. 1985). PBB mixtures were classified as "mixed-type" inducers of hepatic microsomal monooxygenases and... 

The enzyme induction properties of PBDEs have been less studied than for other structurally similar chemicals, but the existing information suggests that they can be classified as mixed-type inducers of hepatic microsomal monooxygenases (Damerud et al. 2001 de Wit 2002 Hardy 2002b). Few studies have examined the structure-induction relationships for PBDEs. Chen et al. (2001) examined the ability of 12 PBDE congeners and 3 commercial mixtures to induce EROD activity in chick and rat hepatocytes, in liver cell lines from rainbow trout, rat, and human, and in a human intestinal cell line. The number of... 

Haake JM, Merrill JC, Safe S. 1985. The in vitro metabolism of benzo [ajpyrene by polychlorinated and polybrominated biphenyl induced rat hepatic microsomal monooxygenases. Can J Physiol Pharmacol 63 1096-1100. 

Imazu, K., Fujishiro, K. Inoue, N. (1992) Effects of dimethylformamide on hepatic microsomal monooxygenase system and glutathione metabolism in rats. Toxicology, ll. 41-50... 

Previously the most used and most reliable of these tests involved the measurement of effects on the hexobarbital sleeping time and the zoxazolamine paralysis time. Both of these drugs are fairly rapidly deactivated by the hepatic microsomal monooxygenase... 

Irreversible inhibition, which is much more important toxicologically, can arise from various causes. In most cases the formation of covalent or other stable bonds or the disruption of the enzyme structure is involved. In these cases the effect cannot be readily reversed in vitro by either dialysis or dilution. The formation of stable inhibitory complexes may involve the prior formation of a reactive intermediate that then interacts with the enzyme. An excellent example of this type of inhibition is the effect of the insecticide synergist piperonyl butoxide (Figure 9.6) on hepatic microsomal monooxygenase activity. This methylenedioxyphenyl compound can form a stable inhibitory complex that blocks CO binding to P450 and also prevents substrate oxidation. This complex results from the formation of a reactive intermediate, which is shown by the fact that the type of inhibition changes from competitive to irreversible as metabolism, in the... 

Hepatic microsomal monooxygenase activity was also studied in several marine species from coastal Maine (Pohl et al., 1974). Table 9.2 shows that microsomal monooxygenase activities varied widely in these species, even though the taxonomic gap is smaller than that shown in Table 9.1. 

Difluoroethylene may interact with the hepatic microsomal monooxygenase to form epoxide. It inhibits microsomal mixed function oxidase in vitro. 

Borlakoglu JT, Wilkins JPG. 1993a. Correlations between the molecular structures of polyhalogenated biphenyls and their metabolism by hepatic microsomal monooxygenases. Comp Biochem Physiol 105C(1) 113-117. 

Takabatake E, Fujita M, Sawa Y. 1980. Combined effects of polychlorinated biphenyls and methylmercury on hepatic microsomal monooxygenases and the hepatic action of bromobenzene. JPharmDyn 3 463-469. 

The effects of 237 in combination with other compounds have been examined. In one study, neither lobeline nor ethyl alcohol were found to be clastogenic in human lymphoblastoid cell cultures. The combination of lobeline with ethyl alcohol, however, produced a marked increase in genetic damage [530]. In another study, the toxicity of 237 in mice was modified by pretreatment with SKF 525-A, phenobarbital, or 3-methylcholanthrene [531]. Pretreatment of mice with SKF 525-A caused a dose-dependent enhancement of lobeline toxicity. Pretreatment with phenobarbital or 3-methylcholanthrene served to decrease the toxicity of 237, suggesting that hepatic microsomal monooxygenases are involved in the detoxification process. 

Means JR, Carlson GP, Schnell RC (1979) Studies on the mechanism of cadmium-induced inhibition of the hepatic microsomal monooxygenase of the male rat. Toxicol Appl Pharmacol 48 293-304... 

---