Effects of inducers and inhibitors on drug-metabolizing enzymes and on drug toxicity in extrahepatic tissues.

When a compound that is removed from the body by metabolism produces toxicity in extrahepatic organs directly, rather than via active metabolites, induction or inhibition of the drug-metabolizing enzymes simply will decrease or enhance, respectively, the toxic effects of the compound. On the other hand, the effects of chemicals whose toxicity depends on their activation by metabolism may be modified in a complex way by pretreatment with inducers or inhibitors of the enzymes; it may, therefore, be impossible to predict the effect of pretreatment on the metabolism and toxicity of a given compound. The major sources of such complexity are that (a) inducers and inhibitors can have multiple effects on pathways of drug toxification or detoxification, both in the liver and in extrahepatic tissues, (b) active metabolites can be formed both in the liver and at extrahepatic sites, and they may not be sufficiently stable for transport from one site to another, and (c) regardless of the effect of pretreatment on pathways of extrahepatic metabolism, the accompanying effects on hepatic metabolism may determine the extrahepatic distribution and site of metabolism (in vivo) of a protoxin or its active metabolite(s). A review of studies on pulmonary toxicity produced by three agents--monocrotaline, bromobenzene, and 4-ipomeanol--illustrates several of these problems, and also shows the value of using inducers and inhibitors in the experimental analysis of extrahepatic toxicity produced by reactive metabolites.

[1]  M. Boyd,et al.  Ipomeanol 4-glucuronide, a major urinary metabolite of 4-ipomeanol in the rat. , 1982, Drug metabolism and disposition: the biological fate of chemicals.

[2]  M. R. Boyd,et al.  Biochemical mechanisms in chemical-induced lung injury: roles of metabolic activation. , 1980, Critical reviews in toxicology.

[3]  C. Wolf,et al.  Cytochrome p-450: localization in rabbit lung. , 1980, Science.

[4]  R. C. Garner Carcinogenesis by fungal products. , 1980, British medical bulletin.

[5]  I. Selikoff,et al.  DECREASE IN VITAL CAPACITY IN PCB‐EXPOSED WORKERS IN A CAPACITOR MANUFACTURING FACILITY * , 1979, Annals of the New York Academy of Sciences.

[6]  G. Hook,et al.  Foreign compound metabolism by isolated cells from rabbit lung. , 1979, Drug metabolism and disposition: the biological fate of chemicals.

[7]  H. Reznik-Schüller,et al.  In vivo autoradiography and nitrosoheptamethyleneimine carcinogenesis in hamsters. , 1979, Cancer research.

[8]  M. Boyd,et al.  In vitro studies on the metabolic activation of the pulmonary toxin, 4-ipomeanol, by rat lung and liver microsomes. , 1978, The Journal of pharmacology and experimental therapeutics.

[9]  M. Boyd,et al.  In vivo studies on the relationship between target organ alkylation and the pulmonary toxicity of a chemically reactive metabolite of 4-ipomeanol. , 1978, The Journal of pharmacology and experimental therapeutics.

[10]  M. Boyd Evidence for the Clara cell as a site of cytochrome P450-dependent mixed-function oxidase activity in lung , 1977, Nature.

[11]  F. Guengerich Separation and purification of multiple forms of microsomal cytochrome P-450. Activities of different forms of cytochrome P-450 towards several compounds of environmental interest. , 1977, The Journal of biological chemistry.

[12]  M. Boyd Role of metabolic activation in the pathogenesis of chemically induced pulmonary disease: mechanism of action of the lung-toxic furan, 4-ipomeanol. , 1976, Environmental health perspectives.

[13]  M. Boyd,et al.  Distribution, excretion, and binding of radioactivity in the rat after intraperitoneal administration of the lung-toxic furan, [14C]4-Ipomeanol. , 1975, Toxicology and applied pharmacology.

[14]  J. Gillette Reactive Metabolites of Organohalogen Compounds , 1975 .

[15]  D. Jollow,et al.  Bromobenzene-induced liver necrosis. Protective role of glutathione and evidence for 3,4-bromobenzene oxide as the hepatotoxic metabolite. , 1974, Pharmacology.

[16]  G. Krishna,et al.  Metabolism and binding of aromatic hydrocarbons in the lung. Relationship to experimental bronchiolar necrosis. , 2015, The American review of respiratory disease.

[17]  A. Walker,et al.  The toxicology of dieldrin (HEOD). II. Comparative long-term oral toxicity studies in mice with dieldrin, DDT, phenobarbitone, -BHC and -BHC. , 1973, Food and cosmetics toxicology.

[18]  J. Allen,et al.  Modifications of pyrrolizidine alkaloid intoxication resulting from altered hepatic microsomal enzymes. , 1972, Toxicology and applied pharmacology.

[19]  I. White,et al.  The conversion of pyrrolizidine alkaloids to N-oxides and to dihydropyrrolizine derivatives by rat-liver microsomes in vitro. , 1971, Chemico-biological interactions.

[20]  E. McLean The toxic actions of pyrrolizidine (senecio) alkaloids. , 1970, Pharmacological reviews.

[21]  W. H. Butler,et al.  Lesions in the liver and lungs of rats given pyrrole derivatives of pyrrolizidine alkaloids , 1970, The Journal of pathology.

[22]  K. Herrold Aflatoxin induced lesions in Syrian hamsters. , 1969, British Journal of Cancer.

[23]  A. Mclean,et al.  Increased susceptibility to carbon tetrachloride poisoning in the rat after pretreatment with oral phenobarbitone. , 1969, Biochemical pharmacology.