Cytochrome P-450 levels

Various minor hematological effects have been noted in animals. Rats exposed to 50-800 ppm of trichloroethylene continuously for 48 or 240 hours showed time- and dose-related depression of delta-aminolevulinate dehydratase activity in liver, bone marrow, and erythrocytes (Fujita et al. 1984 Koizumi et al. 1984). Related effects included increased delta-aminolevulinic acid (ALA) synthetase activity, reduced heme saturation of tryptophan pyrrolase and reduced cytochrome P-450 levels in the liver and increased urinary excretion of... 

The observed mutagenic responses to AFB reflect the overall effects of activation and detoxification systems on the in vitro metabolism of AFB. It appeared that the effect of high casein levels fed to trout was that a greater amount of activated AFB was produced and/or that less could be detoxified by these fish than by those fed lower casein diets. If lowered cytochrome P-450 content and AE activities in fish fed the high casein diets represented a decrease in the activation of AFB, then these effects were overcome by the observed decreases in GTr activity and/or increases in AFB conversion to AFL relative to those of trout fed lower casein diets. Alternately, the results could be explained by dietary effects upon some unknown OAFB metabolizing enzyme system in trout, upon free GSH levels in hepatic tissue, or that the levels of the cytochrome P-450 involved in AFB activation were not reflected by the observed total cytochrome P-450 levels. 

SPMDs compared to oysters explains much of the difference in CFs between the two samphng matrices. Nevertheless, metabolism of these PAHs cannot be ruled out as a causative factor in the observed differences between SPMD and oyster CFs, because cytochrome P-450 levels in some mollusks are fairly high (Buhler and Williams, 1989). 

Goldstein, B. D., S. Solomon, B. S. Pasternack, and D. R. Bickers. Decrease in rabbit lung microsomal cytochrome P-450 levels following ozone exposure. Res. Commun. Chem. Path. Pharmacol. 10 759-762, 1975. 

The carcinogenicity of af la toxin is reduced by protein deficiency, presumably because of reduced metabolic activation to the epoxide intermediate, which may be the ultimate carcinogen, which binds to DNA (Fig. 5.14). A deficiency in dietary fatty acids also decreases the activity of the microsomal enzymes. Thus, ethylmorphine, hexobarbital, and aniline metabolism are decreased, possibly because lipid is required for cytochromes P-450. Thus, a deficiency of essential fatty acids leads to a decline in both cytochromes P-450 levels and activity in vivo. 

Figure 5.30 Development of hepatic reduced glutathione and cytochrome P-450 levels with age in mice. Abbreviations GSH, glutathione ( ) cyt.P450, cytochrome P-450 (A)- Source From Ref. 37.

The converse is true of drugs requiring metabolic activation for toxicity. For example, paracetamol is less hepatotoxic to newborn than to adult mice, as less is metabolically activated in the neonate. This is due to the lower levels of cytochromes P-450 in neonatal liver (Fig. 5.30). Also involved in this is the hepatic level of glutathione, which is required for detoxication. Although levels of this tripeptide are reduced at birth, development is sufficiently in advance of cytochrome P-450 levels to ensure adequate detoxication (Fig. 5.30). The same effect has been observed with the hepatotoxin bromobenzene. (For further details of paracetamol and bromobenzene see chap. 7.) Similarly, carbon tetrachloride is not hepatotoxic in newborn rats as metabolic activation is required for this toxic effect, and the metabolic capability is low in the neonatal rat. 

Reduced synthesis. The synthesis of enzymes may be decreased, resulting in a decrease in the in vivo activity. With cytochrome P-450 there are a number of ways in which this occurs. Thus, administration of the metal cobalt to animals will decrease levels of cytochromes P-450 by inhibiting both the synthesis and increasing the degradation of the enzyme. Thus, cobalt inhibits S-aminolaevulinic acid synthetase, the enzyme involved in heme synthesis. Cobalt will also increase the activity of heme oxygenase, which breaks down the heme portion to biliverdin. The compound 3-amino, 1, 2, 3-triazole decreases cytochromes P-450 levels by inhibiting porphyrin synthesis. 

Magos L, Butler WH, White IN. 1973. Hepatotoxicity of CS2 in rats Relation to postexposure liver weight and pre-exposure cytochrome P-450 level. Biochem Pharmacol 22 992-994. 

Dedifferentiation. A major problem encountered with monolayer cultures of hepatocytes, is that their prolonged use is limited by a change in the activity of certain biotransformation enzymes during the ageing of the cells (for review see (11)). Initially, this was shown for the very important group of cytochrome P-450 related enzyme activities, which often decrease to 50% or more within 24 hr. Subsequent studies also reported changes, both increases and decreases, for other enzymes and enzymatic activities (72, 13, 14, 15). The problem is not restricted to hepatocytes from rats, although in the case of human hepatocytes, the decrease in cytochrome P-450 levels appears to be much slower (6, 16). 

In the field, statistically higher levels of cytochrome P-450 content and fluorometric BPH activity have been observed in hepatopancreas of several crab species from polluted compared to clean reference sites, viz. C sapidus (New Jersey sites, USA) P-450, 700% increase over control site, BPH, 272% U, minax (Savannah river, USA) P-450, 179 to 467%, BPH, 140% (Lee et al. 1982) M. crispata (Istrian coast, Yugoslavia) BPH, 174 to 753% (Bihari et al. 1984). Higher cytochrome P-450 levels and apparent Kg for aniline were indicated in Uca pugilator from oil spill sites in Tampa Bay, Florida, USA (Lee et al. 1981a, 1982). 

Abnormal elevation of HO activity in response to metals and other xenobiotics has both negative and positive consequences for cells. While the physiological role of HO involves the turnover of heme compounds, a protracted increase in the de novo synthesis of HO has been generally associated with perturbation of cellular processes which may lead to cell injury or death. Reduction of heme via HO can deplete cytochrome P-450 levels, inhibit mixed function oxidase activities, and deplete mitochondrial respiratory cytochromes (Maines and Kappas 1977). Cellular respiration and biotransformation of endogenous compounds and xenobiotics may become compromised. 

Ambike, S.H., Baxter, R.M. and Zahid, N.D. (1970) The relationship of cytochrome P-450 levels and alkaloid synthesis in Claviceps purpurea. Phytochemistry, 9,1953-1958. 

Male rats have only 10-20% more microsomal cytochrome P-450 than females yet males metabolize many drugs 3 to 4 times more rapidly than females. On the other hand, after treatment of animals with 3-methylcholanthrene. cytochrome P-450 levels increase 50 to 100% but certain enzyme activities remain unchanged or decrease. 

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