dieldrin and Hypertrophy

Threshold dosages of the photoisomers of cyclodiene insecticides, namely photochlordane, photodieldrin, and photoheptachlor, for the induction of hepatic microsomal cytochrome P450 (P450) and liver hypertrophy in male rats were at least one-quarter of those reported for corresponding parent cyclodienes. Maximum increase in total P450 concentration (30%) and demethylases activities (100%) was always respectively one-third or one-tenth of that reported for parent cyclodienes. The P450 isozymic form induced by photoheptachlor resembled that induced by pentobarbital (P4502B1) in its substrate specificity, spectral characteristics, and electrophoretic mobility. The induction of P450 was initially followed by hepatic hypertrophy. However, higher dosages of photoisomers caused wasting and lowered both the liver weight and the activity of aniline hydroxylase while those of mirex and endrin, which also caused wasting and lowered aniline hydroxylase activity, continued causing further hepatic hypertrophy.

Topics: Aniline Hydroxylase; Animals; Body Weight; Chlordan; Cytochrome P-450 Enzyme System; Dieldrin; Enzyme Induction; Heptachlor; Hypertrophy; Insecticides; Isoenzymes; Liver; Male; Microsomes, Liver; Mirex; Organ Size; Pentobarbital; Rats; Rats, Sprague-Dawley; Substrate Specificity

Chronic exposure of rodents to high dose levels of drugs, food additives and environmental chemicals frequently results in liver enlargement. Several of these compounds have been found to enhance the incidence of liver tumors in animals briefly exposed previously to hepatocarcinogens. Accordingly, it has been advanced that these agents act as tumor promoters. This contention has remained subject of controversy following reports that these substances may also cause liver tumors in noncarcinogen-treated rodents, particularly in those characterized by a relatively high incidence of "spontaneous" liver tumors. Since many of these chemicals are in common use, a crucial question would seem to be whether such effects are due to facilitation of the expression of pre-existing oncogenic potential, i.e., to tumor promotion, or to the synergistic action of weakly carcinogenic agents. As a result of mechanistic differences tumor promotion and syn-carcinogenesis must exhibit different dose-time-response characteristics, and, accordingly, it should be possible, in principle, to discriminate between these phenomena. However, since tumor manifestation periods in low-dose groups frequently exceed the animals average lifespan, this approach may not always yield conclusive data, unless a sensitive early marker of carcinogenic activity can be employed. There is evidence that enzyme-deficient preneoplastic areas in liver can be used for this purpose. A strong quantitative correlation between carcinogen dose, the extent of ATPase deficient areas, and the subsequent appearance of tumors has now been established for a number of hepatocarcinogens. Experimental data are consistent with the concept that two critical events (hits) are required for induction of ATPase deficiency in hepatocytes. The first hit is carcinogen-dependent, whereas the second hit would seem to be due to time-dependent event(s). Tumor-promoters, such as phenobarbital, were found to accelerate and increase formation of preneoplastic islets. This evidence, together with data indicating that the compound is devoid of carcinogenic potential, suggests that phenobarbital may be operative at relatively early stages of hepatocarcinogenesis by increasing the probability of the occurrence of the time-dependent second hit. Such effects are dose-dependent and appear to be related to the induction of liver enlargement. The changes in hepatocellular ploidy status and atypical nuclear figures observed during phenobarbital tr

Topics: Adenosine Triphosphatases; Animals; Biotransformation; Carcinogens; Cocarcinogenesis; Dieldrin; Dose-Response Relationship, Drug; Hypertrophy; Liver; Liver Neoplasms, Experimental; Mice; Phenobarbital; Precancerous Conditions

Topics: Aldrin; Aniline Compounds; Animals; Cytochrome P-450 Enzyme System; Dieldrin; Electron Transport; Endoplasmic Reticulum; Enzyme Induction; Female; Hypertrophy; Male; Microsomes, Liver; Morphine Derivatives; NADH, NADPH Oxidoreductases; NADPH-Ferrihemoprotein Reductase; Organ Size; Rats; Sex Factors; Time Factors

Topics: Animals; Carcinogens; Dieldrin; DNA; Dogs; Endoplasmic Reticulum; Hyperplasia; Hypertrophy; Liver; Mice; Microsomes, Liver; Phenobarbital; Rats; Subcellular Fractions

Topics: Animals; Chemical and Drug Induced Liver Injury; Dieldrin; DNA; Endoplasmic Reticulum; Enzyme Induction; Female; Heme; Histocytochemistry; Hypertrophy; Liver; Microscopy, Electron; Microsomes; Mitochondria, Liver; Mixed Function Oxygenases; Oxidative Phosphorylation; Oxidoreductases; p-Dimethylaminoazobenzene; Proline; Proteins; Rats