Aminopyrine N-demethylase Activity Research Articles

Depression of cytochrome P450-dependent drug biotransformation by poly(rI·rC) and aspirin

The inhibition of hepatic microsomal cytochrome P450 and cytochrome b5 levels by poly(rI.rC) and aspirin in vitro was studied in male Swiss mice. Poly(rI.rC) (10 mg/kg) decreases cytochrome P450 to a level of 61% and cytochrome b5 to 31%, while the activity of aminopyrine demethylase was decreased to 66%. Aspirin (200 mg/kg) decreased the level of cytochrome P450 and cytochrome b5 to 45 and 23%, respectively. Further studies on the effect of poly(rI.rC) showed that this decrease in the levels of cytochromes was mainly due to alteration in the protein synthesis of these hemoproteins.

Growth hormone regulation of hepatic drug-metabolizing enzymes in the mouse

Hepatic microsomal hexobarbital hydroxylase and aminopyrine N-demethylase activities increased in adult male mice following hypophysectomy to female-like levels, eliminating the normal sexually dimorphic pattern of these enzymes. Exogenous growth hormone replacement ( 0.08 I.U. 100 g body weight/day) re-established the lower masculine activities only when administered subcutaneously once every 12 hr. Enzyme activities remained elevated at female-like levels when the same total dose of growth hormone was infused continuously using osmotic pumps or was injected once every 6 hr. These data suggest that, despite the reversed orientation of sex differences in hepatic drug-metabolizing enzymes between rats and mice (i.e. higher enzyme activities in female mice and male rats), the basic hormonal regulatory axis is similar in the two species. Cyclic fluctuations of systemic growth hormone concentrations masculinize kinetic parameters of hepatic hexobarbital hydroxylase and aminopyrine N-demethylase in both species. Rats and mice differ in that these similar hormonal signals lower the apparent V max in male mice, while markedly increasing the enzyme activities in male rats. It appears more likely, therefore, that species- and sex-specific differences in the total hepatic cytochrome P-450 isoenzyme populations produce the reversed sex-dependent pattern of hexobarbital hydroxylase and aminopyrine N-demethylase.

Effect of cimetidine on hepatic biochemical changes, liver toxicity and major urinary metabolite excretion of trichloroethylene in rats.

The effects of cimetidine (CIM) (an inhibitor of the hepatic microsomal monooxygenase system) on the metabolism and hepatotoxicity of trichloroethylene (TRI) were studied in male Sprague-Dawley rats. Rats were given three doses of 120 mg/kg i.p. (low-dose regimen) of CIM at 0, 6 and 11 h for 1 day, or ten doses of 200 mg/kg (high-dose regimen) at 8, 11, 14 and 17 h for 2 days and 8 and 11 h on 3rd day. Trichloroethylene (0.5 or 0.65 ml/kg) was administered i.p. 1 h after 2nd dose (low-dose regimen) or 9th dose (high-dose regimen) of CIM. In the low-dose regimen study, the activity of hepatic microsomal aminopyrine N-demethylase was decreased 1 and 5 h after the second dose and 7 h after the third dose of CIM, but became normal 20 h after the last dose. The cytochrome P-450 content and the activities of aniline hydroxylase and epoxide hydratase remained unchanged. Trichloroethylene at both dose levels produced liver toxicity, as verified by increase in activities of SDH and SGPT as well as by liver histology. Cimetidine alone had no such effect. An apparent reduction in TRI toxicity by CIM (at both dose regimens) could be observed histologically. The biochemical tests (SDH and SGPT) corroborated the histological changes only when TRI was given at a dose of 0.5 ml/kg combined with a high-dose regimen of CIM. Cimetidine at both dose regimens had a tendency to decrease the in vivo metabolism of TRI.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of serum testosterone level with buserelin on the activities of drug and testosterone hydroxylase and on the content of a male-specific form of cytochrome P-450 in male rats

The effects of administration of buserelin, a synthetic agonist of lutenizing hormone-releasing hormone (LH-RH), on the content of P-450-male, a male specific form of cytochrome P-450, and the activities of drug and testosterone hydroxylases were examined in liver microsomes of male rats. Administration of buserelin resulted in a decrease in the serum level of testosterone in a dose-dependent manner. Similar decreases were seen in the activities of aminopyrine N-demethylase, 7-propoxycoumarin O-depropylase and testosterone 2α- and 16α-hydroxylases, but not in the activity of aniline p-hydroxylase. Thus, correlations were observed between the serum level of testosterone and the activities of drug and testosterone hydroxylases except for aniline p-hydroxylase. These results indicate that the drug and testosterone hydroxylases are affected sensitively and sequentially by the changes in the testosterone levels in the body.

Chronic liver injury by thioacetamide and promotion of hepatic carcinogenesis.

To verify whether a mild, but prolonged liver injury by chemicals needing bioactivation causes both hepatic cirrhosis and the appearance of hepatocyte nodules and tumors (providing the liver has been exposed previously to initiating stimuli), diethylnitrosamine-initiated and uninitiated rats were administered thioacetamide at low dose (250 mg/l drinking water) for 6 months. Hepatocyte nodule incidence as well as changes in the drug-metabolizing system were followed at monthly intervals. In the uninitiated rats a micronodular liver cirrhosis slowly developed upon thioacetamide chronic administration; a few hepatocyte focal lesions of small size were seen from the 3rd month onward. By contrast in the diethylnitrosamine-initiated thioacetamide-treated rats the liver was macronodular because of the appearance and growth of many hepatocyte nodules; some hepatomas were also seen. During thioacetamide administration both uninitiated and diethylnitrosamine-initiated rats underwent a progressive decrease of the cytochrome P-450 liver content as well as of the activity of aminopyrine N-demethylase, ethoxycoumarin O-deethylase and ethoxyresorufin O-deethylase. On the other hand, most components of the phase II of the drug-metabolizing system were markedly enhanced. In conclusion, chronic administration of thioacetamide at low doses provided strong promoting stimuli for previously initiated hepatocytes.

Effects of bromocriptine on hepatic cytochrome P-450 monooxygenase system.

We have evaluated the in vitro effects of bromocriptine (Br), on the hepatic cytochrome P-450 monooxygenase system of rats pretreated with saline phenobarbitone (PB) and beta-naphthoflavone (BNF). Br inhibited ethoxyresorufin O-dealkylase (EROD) activity in liver microsomes of rats pretreated with saline and PB but not in BNF pretreated animals. Maximum inhibition of EROD activity by Br in the microsomes of saline and PB pretreated rats were 50%-60% of the control. In contrast, a dual effect was observed on aminopyrine N-demethylase activity (APD) by Br in microsomes of saline, PB and BNF pretreated rats. At a low concentration (25 microM), Br inhibited the activity of APD to a similar extent in all pretreatment groups; however, with higher concentrations of Br (50 microM to 300 microM), enhancement of APD activity was observed. Br (300 microM) increased the APD activity to 2-3 times the control level in microsomes of rats pretreated with saline, PB or BNF. Spectral studies revealed a Type II binding of Br to cytochrome P-450 from microsomes of saline and PB pretreated rats. A reverse type I binding was observed for BNF induced microsomes. In addition, Br also enhanced NADPH cytochrome c (P-450) reductase activity to a similar extent in all pretreatment groups. These results suggest that the inhibition of EROD activity may be due to direct binding by Br to certain isozymes of cytochrome P-450 and that the enhancing effect of Br on APD activity may be in part due to the activation of the NADPH cytochrome c reductase component of the cytochrome P-450 monooxygenase system.

Hepatic blood flow and drug metabolism in glycerol-rechallenged rats

To analyze the hepatic blood flow and drug metabolism during glycerol-induced acute renal failure, 24 male Wistar rats were randomly divided into three groups: Group I received an intra-muscular injection of 1 ml/100 g body weight 50% glycerol, group II a second injection on day 14 and group III a second injection on day 42 after the first injection respectively. The inulin clearance, the aminopyrine N-demethylase activity, the NADPH-cytochrome P-450 activity and the cardiac output and blood flow to the organs were measured before and after glycerol injection. The total hepatic and renal blood flow decreased less significantly in group II compared to group I and III. Various P 450 activities were kept on a high level only in group II. This observation indicates that the maintenance not only of renal but also of hepatic blood flow plays an important role in preventing the development of glycerol-induced acute renal failure. The mechanism may be the induction of various P 450 activities resulting in an increased hepatic clearance of nephrotoxic substances.

Effects of Bromocriptine on Hepatic Cytochrome P-450 Monooxygenase System

We have evaluated the in vitro effects of bromocriptine (Br), on the hepatic cytochrome P-450 monooxygenase system of rats pretreated with saline phenobarbitone (PB) and β-naphthoflavone (BNF). Br inhibited ethoxyresorufin O-dealkylase (EROD) activity in liver microsomes of rats pretreated with saline and PB but not in BNF pretreated animals. Maximum inhibition of EROD activity by Br in the microsomes of saline and PB pretreated rats were 50%-60% of the control. In contrast, a dual effect was observed on aminopyrine N-demethylase activity (APD) by Br in microsomes of saline, PB and BNF pretreated rats. At a low concentration (25 μM). Br inhibited the activity of APD to a similar extent in all pretreatment groups; however, with higher concentrations of Br (50 μM to 300μM). enhancement of APD activity was observed. Br (300 μM) increased the APD activity to 2–3 times the control level in microsomes of rats pretreated with saline, PB or BNF. Spectral studies revealed a Type II binding of Br to cytochrome P-450 from microsomes of saline and PB pretreated rats. A reverse type I binding was observed for BNF induced microsomes. In addition, Br also enhanced NADPH cytochrome c (P-450) reductase activity to a similar extent in all pretreatment groups. These results suggest that the inhibition of EROD activity may be due to direct binding by Br to certain isozymes of cytochrome P-450 and that the enhancing effect of Br on APD activity may be in part due to the activation of the NADPH cytochrome c reductase component of the cytochrome P-450 monooxygenase system.

Acute Effect of Amitriptyline, Phenobarbital or Cobaltous Chloride on δ-Aminolevulinic Acid Synthetase, Heme Oxygenase and Microsomal Heme Content and Drug Metabolism in Rat Liver

Cobaltous chloride (CoCI2) caused very marked decreases of cytochrome P-450, b5 and total heme contents and an increase of heme oxygenase activity. On the contrary, phenobarbital (PB) increased hepatic drug-metabolizing enzymes, but the total heme content remained unchanged. On the other hand, amitriptyline (AMT) caused a marked increase of δ-aminolevulinic acid (δ-ALA) synthetase activity at 12 and 24 hr. In addition, the contents of total heme and cytochrome b5 and the activities of aminopyrine (AM) N-demethylase and aniline (AN) hydroxylase at 24 hr were also increased by AMT, whereas cytochrome P-450 content did not change. This may be explained by the fact that AMT would increase hepatic heme synthesis through the prolonged induction of d-ALA synthetase, but it may not cause an increase in cytochrome P-450 heme because there are increases in the contents of cytochrome b5 and total heme.

Acute effect of amitriptyline, phenobarbital or cobaltous chloride on delta-aminolevulinic acid synthetase, heme oxygenase and microsomal heme content and drug metabolism in rat liver.

Cobaltous chloride (CoCl2) caused very marked decreases of cytochrome P-450, b5 and total heme contents and an increase of heme oxygenase activity. On the contrary, phenobarbital (PB) increased hepatic drug-metabolizing enzymes, but the total heme content remained unchanged. On the other hand, amitriptyline (AMT) caused a marked increase of delta-aminolevulinic acid (delta-ALA) synthetase activity at 12 and 24 hr. In addition, the contents of total heme and cytochrome b5 and the activities of aminopyrine (AM) N-demethylase and aniline (AN) hydroxylase at 24 hr were also increased by AMT, whereas cytochrome P-450 content did not change. This may be explained by the fact that AMT would increase hepatic heme synthesis through the prolonged induction of delta-ALA synthetase, but it may not cause an increase in cytochrome P-450 heme because there are increases in the contents of cytochrome b5 and total heme.

The effects of perfluorodecanoic acid on hepatic stearoyl-coenzyme A desaturase and mixed function oxidase activities in rats

Perfluorodecanoic acid (PFDA) causes a dioxin-like toxic syndrome and alters the hepatic oleate/stearate ratio in rats. The acute toxic effects of a single ip dose (50 mg/kg) of PFDA on hepatic stearoyl-CoA desaturase and mixed function oxidases were studied in male Fischer-344 rats, 14 days after dosing. PFDA causes a marked decrease in food intake in rats, resulting in severe body weight loss with delayed lethality (2–3 weeks after dosing). To distinguish the effects of hypophagia from those caused by PFDA, pairfed control rats were used in addition to ad libitum-fed controls. Stearoyl-CoA desaturase activity, responsible for the conversion of stearoyl-CoA to oleoyl-CoA, was absent in both PFDA-dosed rats and their pair-fed controls at Day 14. Electron transfer through the desaturase system was significantly reduced in PFDA-treated rats only, and in these rats there was a significant reduction in microsomal cytochrome b 5, an important component of this electron transfer system. Pentobarbital sleeping times were significantly prolonged in both the PFDA-dosed and pair-fed rats, as compared with the ad libitum-fed controls. This effect was more pronounced in PFDA-dosed rats. Waking plasma pentobarbital concentration was similar in all treatment groups. Hepatic microsomal cytochrome P-450 content was unaffected. Aminopyrine N-demethylase activity was greatly reduced in PFDA-dosed rats. Although pair-fed controls also had reduced demethylase activity, it was not as pronounced as in PFDA-dosed rats, and was probably due to the fasted condition of these animals. Although the mechanism of action of PFDA is not known, it is possible that PFDA affects microsomal enzymes by altering the structure and/or function of the membranes in which they are located, through effects on lipid metabolism.

Effects of bile duct obstruction and decompression on hepatic microsomal mixed function oxidase system in rats

The effects of biliary obstruction and drainage on the hepatic microsomal mixed function oxidase system were studied in rats. Bile duct obstruction produced a significant reduction in the hepatic cytochrome P-450 dependent mixed function oxidase system. After release of the bile duct obstruction, the reduction in microsomal enzymes was practically reversible; however, the process of recovery was slow and differed with the microsomal enzymes in question. Increases in cytochrome b 5 content and NADH-cytochrome b 5 reductase activity were slower than increases in cytochrome P-450 content and NADPH-cytochrome c reductase activity. Aniline hydroxylase activity increased more rapidly and corresponded to cytochrome P-450 contents more so than did the aminopyrine demethylase activity. After the release of bile duct obstruction, however, the bile acids which had accumulated in the liver during cholestasis were reduced rapidly, to a normal range. These results suggest that there is a discrepancy between reductions in hepatic bile acids and those in the hepatic microsomal mixed function oxidase system after biliary decompression.

Effect of caffeine on the hepatic microsomal mixed function oxidase system during phenobarbital and benzo[ a] pyrene treatment in rats

Simultaneous administration of caffeine (100 mg/kg, i.p., 3 days) and phenobarbital (80 mg/kg, i.p., 3 days) to adult male rats resulted in a significant decrease in hepatic cytochrome P-450 and acetanilide hydroxylase activity, compared to phenobarbital administration alone. While simultaneous administration of caffeine and benzo[ a]pyrene (20 mg/kg, i.p., 2 days) increased acetanilide hydroxylase, compared to benzo[ a]pyrene administration, no change was seen in the cytochrome P-450 concentration. In vitro addition of 2.5 mM caffeine to microsomal incubations from untreated, phenobarbital- and benzo[ a]pyrene-treated rats inhibited aminopyrine N-demethylase activity. No significant difference was seen in the extent of aminopyrine N-demethylase inhibition due to the in vitro addition of caffeine to microsomes from untreated or phenobarbital-treated rats, whereas inhibition in microsomes from benzo[ a]pyrene-treated rats was greater.

Induction of xenobiotic biotransformation by the insecticide chlordimeform, a metabolite 4-chloro- o-toluidine and a structurally related chemical o-toluidine

Chlordimeform, 4-chloro- o-toluidine and o-toluidine have all been found to have carcinogenic properties. Due to an empirical link between such properties and alteration of some biotransformation enzymes, the abilities of these three chemicals to affect cytochrome P-450 mediated biotransformation, epoxide hydrolase and glutathione S-transferase have been examined. Chlordimeform had no effect on the cytochrome P-450 content, aniline p-hydroxylase or glutathione S-transferase activities, but induced ethoxyresorufin- O-deethylase, ethoxycoumarin- O-deethylase and epoxide hydrolase activities and decreased aldrin epoxidase and aminopyrine N-demethylase activities. The metabolite 4-chloro- o-toluidine increased cytochrome P-450, ethoxyresorufin- O-deethylase, ethoxycoumarin- O-deethylase, glutathione S-transferase and epoxide hydrolase activities. o-Toluidine induced cytochrome P-450, ethoxyresorufin- O-deethylase, ethoxycoumarin- O-deethylase, and aldrin epoxidase activities. Ethoxyresorufin- O-deethylase activity was induced approximately eight times by Chlordimeform and 18 times by 4-chloro- o-toluidine and o-toluidine. Induction was seen at 50mg/kg with Chlordimeform and at 10 mg/kg with the other treatments. Chlordimeform increased the 7α and 16α androstenedione hydroxy-lase pathways. 4-Chloro- o-toluidine increased the 7α, 16β and 16α hydroxylase pathways, while o-toluidine increased the 7α, 6β, 16β and 16α hydroxylase pathways. All three chemicals marginally decreased the testosterone pathways. SDS-PAGE of rat microsomes revealed an increase in a protein band of MW c54,000 for the Chlordimeform and 4-chloro- o-toluidine treated groups. Taken together with the increase in ethoxyresorufin- O-deethylase activity these observations are consistent with the induction of hepatic isozyme P-450d. Thus each chemical has been shown to induce various pathways of biotransformation with increases in the P-450c and P-450d specific substrate ethoxyresorufin- O-deethylase being a consistent finding.

Inhibitory effect of zinc-protoporphyrin on the induction of heme oxygenase and the associated decrease in cytochrome P-450 content in rats

Pretreatment of rats with zinc-protoporphyrin, which has shown to be a potent competitive inhibitor of heme oxygenase, resulted in the inhibition of bromobenzene-mediated induction of heme oxygenase and decreases of the cytochrome P-450 content, aminopyrine demethylase and aniline hydroxylase activities. Such an inhibitory effect of zinc-protoporphyrin on the induction of heme oxygenase and concomitant decreases of drug-metabolizing enzymes occurred in a dose-dependent manner with complete inhibition of these effects at a dose of 40 μmol/kg. The effects of zinc-protoporphyrin were also observed in thioacetamide- and BCG-treated rats and ascitic tumor AH 66-bearing rats. Likewise, a decrease of cytochrome b 5 content observed under these experimental conditions was also restored significantly by zinc-protoporphyrin. These results strongly suggest that the induction of heme oxygenase is a primarily important early event which consequently leads to the decrease in cytochrome P-450 content and associated enzyme activities.

EDTA affects cytochrome P450-dependent biotransformation reactions during incubations for the liver microsomal assay

In order to optimize the condition of the liver microsomal assay (LMA), studies were carried out to determine the effects of EDTA on mixed-function oxidase activity and its stability under the exact incubation conditions for the LMA. Aminopyrine N-demethylase (APD) and p-nitroanisole O-demethylase (p-NAD) activities as well as lipid peroxidation development (LP) in S9 liver fractions from β-naphthoflavone and sodium phenobarbital (β-NF + PB)- or Aroclor 1254 (AC)-treated mice were examined during a period of preincubation with EDTA ranging from 1 to 40 mM. At 5 mM EDTA, we obtained a strong inhibition of the microsomal LP as well as the greatest value of the mean specific activity ( A sp) for both APD and pNAD activities. In agreement with the biochemical data, the presence of 5 mM EDTA in the incubation mixtures for the LMA significantly increased the mitotic gene conversion, mitotic crossing-over and point-reverse mutation of the well-known premutagen cyclophosphamide (30 mM) on the diploid D7 strain of Saccharomyces cerevisiae as the outcome of a greater metabolic activity. We concluded that the systematic use of 5 mM EDTA in LMA mixtures could improve the reliability and sensitivity of such a test.

An immunotoxicological evaluation of 4,4′-thiobis-(6- t-butyl- m-cresol) in female B6C3F1 mice : 1. Body and organ weights, hematology, serum chemistries, bone marrow cellularity, and hepatic microsomal parameters

Adult female B6C3F1 mice were gavaged with 4,4′-thiobis-(6- t-butyl- m-cresol) (TBBC) in corn oil at doses of 10, 100, or 200 mg/kg daily for 14 consecutive days. There was no overt toxicity, as manifested by grossly observable behavioral changes, decreased growth rate over the exposure period, or mortality. There were also no marked effects on serum chemistries or hematology, with the exception of a significant increase (41%) in the number of leukocytes at the highest dose. Absolute differential counts indicated that significant increases occurred in the number of lymphocytes (31%) and neutrophils (177%). Studies with bone marrow indicated a significant 30% increase in the number of cells/femur from animals treated with the highest dose of TBBC. The number of macrophage progenitors (CFU-M)/femur was significantly increased by 28%, while the number of granulocyte-monocyte progenitors (CFU-GM)/femur was nonsignificantly increased by 20% in the high dose animals. The weight of both the spleen and liver was increased in a dose-related fashion, although the histopathology of the spleen of TBBC-treated mice was not different from control. The livers of mice receiving the high dose showed mild focal hydropic degeneration, mild hepatitis, and a slight increase in the number of Kupffer cells. No other organs were affected. Liver microsomal protein and cytochrome P-450 levels were increased in a dose-related fashion. Enzyme activities of aminopyrine demethylase and aniline hydroxylase, but not arylhydrocarbon hydroxylase, were also increased in a dose-related fashion.

Effect of glutathione depletion on aminopyrine and formaldehyde metabolism

In previous studies, diethylmaleate (DEM)- and phorone-induced hepatic glutathione (GSH) depletion in rats was accompanied by impaired evolution of 14CO 2 from the N- 14C-labeled methyl groups of aminopyrine, which in turn was attributed to impaired generation of formaldehyde, its subsequent oxidation to formate, or to some combination of both. In the present study, l-buthionine sulfoximine (BSO)-induced hepatic GSH depletion was also accompanied by decreased evolution of CO 2 from aminopyrine, but the extent of the fall in CO 2 was less than that induced by DEM or phorone, even though the decrease in hepatic GSH was comparable with all three GSH-lowering compounds. Incubation of freshly prepared normal hepatic microsomes in vitro with the GSH-lowering agents resulted in impaired aminopyrine- N-demethylase (APDM) activity with inhibition by phorone > DEM > BSO. By contrast, hepatic microsomes prepared from rats pretreated with these compounds had normal APDM activity. 14CO 2 evolution from i.p. administered [ 14C]formaldehyde was not impaired by any of the GSH-lowering compounds. Thus, assessment of APDM activity and formaldehyde metabolism did not unequivocally establish the mechanism(s) by which CO 2 evolution from aminopyrine is depressed by DEM, phorone and BSO, although low GSH is likely to impair metabolism of formaldehyde formed in liver after demethylation of aminopyrine. Quantitative differences in the degree of depression of CO 2 evolution suggest that at least DEM and phorone exert an additional inhibitory effect by a GSH-independent mechanism. This may involve inhibition of aminopyrine- N-demethylase activity.

Effect of diethyl maleate on hepatic ornithine decarboxylase

Diethyl maleate (DEM), a well-known glutathione (GSH) depletor, causes a dose-dependent increase in hepatic ornithine decarboxylase (ODC) activity as well as heme oxygenase activity in rats. Considering the important role ODC has in polyamine biosynthesis in response to endogenous and exogenous stimuli, further extensive studies on the effect of DEM on ODC in relation to its GSH-depleting effect were carried out. Specifically, concomitant with the profound decrease in GSH content, the higher dose of DEM (1284 mg/kg) caused a marked increase in ODC activity (about 1000 times that of the control) at 12 hr after its administration. DEM at this dose also caused a marked increase in heme oxygenase activity, but the effects on cytochrome P-450 content and aminopyrine demethylase activity were less extensive. The increases in ODC and heme oxygenase activities evoked by DEM were almost completely blocked by pretreatment of rats with either actinomycin D or cycloheximide. Parallel to the increase in ODC activity, DEM caused a profound increase in putrescine content in the liver, while the agent reduced spermine content. The administrations of α-difluoromethylornithine and 1,3-diaminopropane resulted in the inhibition of DEM-mediated induction of ODC, but not heme oxygenase. In contrast, methylglyoxal bis(guanylhydrazone) inhibited the induction of both ODC and heme oxygenase evoked by DEM. The DEM-induced ODC exhibited two phases of decay with the prolonged half-lives of 26 and 223 min. Additionally, the elution profile from DEAE-Sepharose CL-6B column chromatography of cytoplasmic fraction from DEM-treated rat liver exhibited two peaks of ODC activity. These findings add new insight into the biochemical effect of DEM on hepatic polyamine metabolism in addition to its GSH-depleting effect.

Effects of a testicotoxic dose of cadmium on the liver and drug metabolism in the rat

1. The effect of an acute testicotoxic dose of cadmium (CdCl 2.H 2O, 2.0 mg/kg i.p.) on liver morphology and drug-metabolizing enzyme activities were studied in adult male and female rats. 2. Cd treatment to female rats caused a slight and reversible decrease in hepatic microsomal aryl hydrocarbon hydroxylase (AHH) and aminopyrine N-demethylase (APND) activities. 3. No significant changes were noted in the liver morphology, serum alanine aminotransferase activities, enzyme induction by phenobarbital and 3-methylcholanthrene, and glucuronosyl-transferase (GT) and glutathione S-transferase (GST) activities. 4. The same Cd treatment to male rats, however, resulted in a much more pronounced and prolonged reduction in AHH and APND activities, which was attributable to a Cd-induced testicular necrosis and, hence, impairment of androgen secretion. 5. Accordingly, Cd treatment to castrated male rats did not lower the enzyme activities any further, and full recovery of activities was obtained after the administration of testosterone. 6. Both GT and GST, the two sex-independent enzymes, were not significantly affected by either Cd or gonadectomy in the male rat. 7. The present data show that a low acute dose of Cd induces chemical castration without severely altering hepatic function.