Lead intoxication: Effects on cytochrome P-450-mediated hepatic oxidations Acute administration of lead to rats caused significant decreases in cytochrome P-450, ethylmorphine N-demethylase, and aniline hydroxylase activities and prolonged hexobarbital-induced sleeping times. However, chronic administration of lead to weanling rats caused no significant changes in hepatic cytochrome P-450 levels or in the microsomal oxidative enzymes over a 12-wk period. Eight patients exposed to lead in the process of burning through lead-painted steel structures for at least 3 mo showed marked effects of chronic lead intoxication on the erythropoietic system: inhibition of erythrocyte o-aminolevulinic acid dehydratase, increased erythrocyte protoporphyrin levels, and increased urinary excretion of o-aminolevulinic acid. Chelation therapy greatly alleviated the inhibitory effects on dehydratase activity and decreased urinary o-aminolevulinic acid excretion. The plasma elimination rate of antipyrine, a drug primarily metabolized by hepatic microsomal enzymes, was determined in the 8 subjects prior to and following chelation therapy. In 7 of 8 subjects, chelation therapy shortened the antipyrine half-lives, but the effect was minimal. These studies show that chronic lead exposure results in significant hematopoietic inhibition of the heme biosynthetic pathway without causing significant changes in hepatic cytochrome P-450-associated enzymic activities.

Alvito P. Alvares, Ph.D.,* Alf Fischbein, M.D., Shigeru Sassa, M.D.,** Karl E. Anderson, M.D., and Attallah Kappas, M.D. New York, N. Y. The Rockefeller University and Environmental Sciences Laboratory, Mount Sinai School of Medicine, City University of New York

Lead toxicity occurs in many industrial workers as well as in children. Types of industries with potential lead hazard range from the manufacture of storage batteries to wrecking and salSupported by United States Public Health Service Grants Nos. ES 01055 and ES 00928. Received for publication July 21. 1975. Accepted for publication Oct. 22. 1975. Reprint requests to: Dr. Alvito P. Alvares. Rockefeller University. New York. N. Y. 10021.

* Recipient of a Research Career Development Award. I K04 ES 000 I 0-0 1. from the National Institutes of Health. ** Recipient of a Career Scientist Award HRC 1-768 of the City of New York.

vage operations involving volatilization of lead paint by acetylene torches. The danger arises from ingestion and inhalation of lead. Although most accidental exposures to lead are by ingestion (e.g., in children), most industrial exposures are to fumes or lead particles in the atmosphere. A major manifestation of lead toxicity is its effect on the hematopoietic system. The ability of lead to impair he me synthesis in erythroid cells is well known, as are the hematologic consequences. 7 In heme biosynthesis, lead inhibits the conversion of 8-aminolevulinic acid 183


Alvares et al.

Clinical Pharmacology and Therapeutics

Table I. Effect of PbCl 2 on cytochrome P-450, microsomal oxidations of ethylmorphine and aniline, and on hexobarbital-induced sleeping time in rats PbCI 2 , 10 mg/kg, single inj. %




0.254t ± 0.025



0.346* ± 0.014

Ethylmorphine N-demethyla se (/Lmol HCHO/mg protein I hr) Aniline hydroxylase (nmol p-aminophenol/mg protein I hr) Cytochrome P-450 (nmol/mg protein) Hexobarbital sleeping time (min)


0.687 ± 0.019


0.545t ± 0.026

± 4



31.90t ± 3.37

± 1.55



± 13

*Each value represents mean ± SE for 5 rats. tValues significantly different from their respective controls (p < 0.05).

Table 11. Effect of chronic administration of Pb acetate on cytochrome P-450 and microsomal oxidations in livers of rats 6 wk

3 wk Measurement

Body weight (gm) Microsomal protein (mg/gm liver) Ethylmorphine Ndemethylase (/Lmol HCHO formed I mg protein/hr) Aniline hydroxylase (nmol p-aminophenol formed/mg protein Ihr ) Cytochrome P-450 (nmol/mg protein)


210* 23.6

± 6 ± 0.6

0.325 ± 0.035 47.77

::t 3.08

0.813 ± 0.043



165t 24.9 0.293 52.12

± 9 ± 0.8 ± 0.010

± 1.40

0.856 ± 0.023


333 ± 6 24.54 ± 1.11 0.337 ± 0.017 41.52 ± 1.97 0.759 ± 0.024


Treated ± 14 292t 23.64 ::t 0.47

0.366::t 0.036 42.63



O.77I::t 0.044

Rats initially weighing 35 to 40 gm were fed a chow diet containing 2 % lead acetate (w I w) for 3, 6, or 12 wk. Controls received a normal rat chow diet. *Each value represents mean ± SE for 5 rats. tValues significantly different from respective control values (p < 0.05).

(ALA) to porphobilinogen (PBG), which is catalyzed by the enzyme o-aminolevulinic acid dehydratase (ALAD). Lead has also been shown to inhibit the enzyme ferrochelatase, which catalyzes the formation of he me from iron and protoporphyrin (PROTO). Thus, lead poisoning can lead to accumulation of PROTO in red blood cells, an increase in ALA in blood and urine, inhibition of blood ALAD, and an increased proportion of immature red cells (reticulocytes and basophilic stippled cells) in blood. The log of ALAD activity in red blood

cells correlates inversely with blood lead levels 8 ; hence, inhibition of ALAD activity is a sensitive indicator of lead poisoning. A substantial fraction of the heme synthesized in liver serves as the prosthetic group of the microsomal hemeprotein, cytochrome P-450. This hemeprotein is the terminal oxidase of the mixed-function oxidase system in the liver, which is involved in the hepatic biotransformation of medicaments, hormones, and many environmental chemicals. The possibility that lead may impair heme synthesis or the

Lead intoxication

Volume 19 Number 2

PbCI 2 • 10 mg Ikg. 2 x 2 days

PbCI 2• 5 mg Ikg. 2 x 2 days Controls

0.300 ± 0.043 39.60 ± 3.34 0.664 ± 0.067 34

± 7



% change


0.156t ± 0.031


29.26t ± 2.66


0.455t ± 0.027 79t

± 7


12 wk Controls

428 26.9

± 9 ± 0.7

0.301 ± 0.008 38.26 ± 3.17 0.739 ± 0.042


410 27.5

± 7 ± 0.9

0.276 ± 0.012 29.43


± 2.65

0.798 ± 0.043


0.299 ± 0.009 41.38 ± 2.43 0.624 ± 0.016 32

± 8



0.195t ± 0.005 25.53t

± 1.21

0.463t ± 0.024 81t

± 8


% change

-35 -38 -26

+ 153

is to study the plasma elimination rate (Ph) of antipyrine, a drug that is completely absorbed when given orally and is completely metabolized by the liver microsomal enzyme system. 5 Antipyrine Ph was determined in 8 lead-poisoned male adults who had had excessive exposure to lead while burning with acetylene torches through lead-painted steel structures in shipyard ways with inadequate protective respiratory equipment. Blood lead levels in these adults ranged from 80 fLg/1OO ml to 180 fLg/ 100 ml whole blood. All subjects showed positive biochemical manifestations of chronic lead poisoning, i.e., depressed ALAD activity and high PROTO concentration in erythrocytes. Antipyrine TV2 was determined in each subject before and after chelation therapy. Materials and methods

function of hemeproteins, such as cytochrome P-450, in the liver has not been studied in great detail. Preliminary studies from this laboratory showed acute lead intoxication to be associated with significant depression in cytochrome P-450 content as well as mixed-function oxidations coupled to the P-450 system. 2 In our study we compared the effects of acute and chronic administration of lead to rats on the cytochrome P-450 system. A feasible way to assess the functional capacity of the cytochrome P-450 system in man

Male Sprague-Dawley rats weighing 150 to 180 gm were used in the acute experiments. Lead chloride, dissolved in 0.9% NaCl solution, was administered at the dosages indicated. Rats were sacrificed 24 hr after the administration of the last dose of lead. In the chronic studies, rat chow diet containing 2% lead acetate was fed to rats, initially weighing 34 to 40 gm, for 12 wk. The rats were sacrificed at 3, 6, and 12 wk. Livers were removed and microsomes were prepared as described previously! and suspended in 0.1 M phosphate buffer, each milliliter containing the equivalent


Alvares et al.

Clinical Pharmacology and Therapeutics



E 01


c £

01 Q)



>. "0


en 100








Weeks on diet Fig. 1. Weight of rats on a 2% lead acetate diet. Rats weighing 35 to 40 gm were fed chow diet containing 2% lead acetate (w/w). Controls received a normal rat chow diet.

of 250 mg of liver (wet weight). The composition of the incubation mixture for the determination of ethylmorphine N-demethylase was similar to that described previously, 1 except that nicotinamide was omitted from the incubation mixture. Formaldehyde formed from the N-demethylation reaction was measured by the method of Nash 13 as modified by Anders and Mannering. 4 Aniline hydroxylase activity was measured by the method of Imai, Ito, and Sato.9 Cytochrome P-450 content was assayed by the method of Omura and Sato,14 using an extinction coefficient of 91mM-1 cm- 1 between 450 and 490 nm. To determine the hexobarbital-induced sleeping times, sodium hexobarbital was administered intraperitoneally at a dosage of lOO mg/kg, and the time of loss of the righting reflex was determined. Protein was determined by the method of Lowry and associates,l1 using bovine serum albumin as a standard.

In the human studies, blood lead determinations were performed by atomic absorption spectroscopy in the New York City Department of Health Laboratories. Blood PROTO levels and ALAD activities were determined by the method of Sassa and associates 18 and Granick and associates,8 respectively. Urinary ALA was determined by the method of Mauzerall and Granick. 12 To determine the T1,6 of antipyrine, the drug was dissolved in syrup and administered orally at a dosage of 18 mg/kg. Heparinized blood samples were collected 3, 6,9, 12, and 15 hr after administration. Plasma antipyrine levels were determined by the method of Brodie and associates. 6 All samples were analyzed in duplicate and the TV2 of the drug was determined from the linear portion of the plot of plasma values on semilog paper. Leadpoisoned patients were treated with CaEDT A (calcium disodium versenate). One gm of CaEDT A was diluted with 500 ml of sterile 5% dextrose solution in water and administered intravenously by slow infusion (45 min to I hr) twice daily for 5 days. One week after CaEDT A treatment, blood lead, PROTO, and ALAD levels were repeated and the antipyrine T1/2 was determined again. The 8 patients were exposed to volatilized lead for at least 3 mo prior to the initiation of this study. None was exposed to lead for the duration of the study. Results

Effect of acute lead administration on hepatic microsomal oxidations in the rat. Ethylmorphine and aniline were chosen as substrates in these studies because they are representative of type I and type 11 substrates. These classes of substrates interact with the microsomal hemeprotein, cytochrome P-450, to give characteristic difference spectra: Amax, 385390 nm; Amin, 418-427 nm for type I substrates; Amax, 425-430 nm; and Amin, 390-405 nm for type 11 interactionsY As shown in Table I, following intraperitoneal administration of various dosages of PbCI 2, there was a 20% to 30% decrease in cytochrome P-450 content in hepatic microsomes 24 hr after the last injection of lead. Concomitant with the decrease in the hemeprotein content, there

Lead intoxication

Volume 19 Number 2


Table Ill. Clinical data on lead-poisoned workers Subject




48 31 24 46 28 38 46 49

B. O. D. D. G. H. H. R. K. S. M.R. M. D. S. E.




Basophilic stippling



Clinical symptoms






+ + + +




+ +


*L: 1.5 packs/day. tL: 1 drink/day; M: 2-3 drinks/day; H: >3 drinks/day. :/: Nausea, epigastric pain, headache, feeling of exhaustion, metal-fume fever.

Table IV. Biochemical data on lead-poisoned workers prior to and following chelation therapy Blood lead (JLg /100 ml) Subject

B. O. D. D. G. H. H. R. K. S. M. R. M. D. S. E.




180 128 106 113 101 85 85 91

ALA excretion (mg /24 hr urine)

Hematocrit (0/0)





68.0 35.0 28.6 27.6 31.6 30.2 42.2 24.2


60 65 55 52 55 47 10-24

I After 10.0 6.9 7.8 9.5 6.9 4.5 5.7 4.4


I After

45.5 50.0 42.0 40.5 43.0 42.0 45.0 45.0 42-51

38.0 41.5 40.5 38.5 42.5 43.0 43.0 45.0

PROTO (JLg/ 100 ml RBC) Before

I After

683 819 930 607 647 644 385 478 48-75

766 680 925 658 649 578 414 504

ALAD (nmol PBG/ml RBC /hr) Before

176 248 197 136 295 128 107 239

I After 407 622 559 459 649 334 414 659


*Ranges for 10 nonnal individuals.

were marked decreases in the in vitro ethylmorphine N-demethylase and aniline hydroxylase activities. After administration of hexobarbital there was a significant prolongation of sleeping times in rats pretreated with PbCl 2 over that in control animals (Table I). There appeared to be no dose-response relationship; a single dose of 10 mg/kg gave responses similar to those after PbCI 2 , 10 mg/kg twice a day for 2 days. Our findings demonstrate that acute administration of lead to animals can cause decreased cytochrome P-450 and associated enzyme activities.

Effect of chronic lead administration on body weight and on hepatic microsomal oxidations in the rat. Body weight changes of weanling rats fed a 2% lead acetate diet are shown in Fig. 1. After 3 wk on the lead diet,

body weight was 21 % lower than that of rats on a normal chow diet. After 3 wk on the diet, the rate of body weight gain was similar in both groups, but significant differences in body weights between the two groups persisted for about 9 to 10 wk. At 12 wk, although body weights of lead-treated rats were lower than those of control animals the difference was not statistically significant. The effects of administration of lead in the diet on cytochrome P-450 and microsomal oxidations is shown in Table 11. Chronic administration of lead to weanling rats over a 12-wk period resulted in no significant differences in microsomal protein, in cytochrome P-450 content, or in ethylmorphine N-demethylase or aniline hydroxylase activities. Thus, daily oral administration of lead to rats had no

Alvares et al.



Clinical Pharmacology and Therapeutics

POST-EDTA Subjects 0


.'" 0




c: N





Fig. 2. Antipyrine half-lives in 8 lead-intoxicated adults before and after chelation. The half-lives were determined before and I wk after the intravenous administration of 1 gm of CaEDTA twice a day for 5 days.

adverse effects on the cytochrome P-450mediated enzyme systems. Effects of chronic occupational exposure to lead on heme-biosynthetic enzymes in man. The 8 workers who had been exposed to lead had blood lead concentrations of 85 to 180 ILg/100 ml blood; their clinical data are shown in Table Ill. Basophilic stippling of red cells in the peripheral circulation was found in all but subjects D. D. and M. D. The biochemical data prior to and following chelation therapy with CaEDT A are shown in Table IV. For comparison, data on 10 normal individuals are also presented. All of the leadintoxicated subjects had increased urinary excretion of ALA, inhibition of erythrocyte ALAD, and increased PROTO levels, as well as highly elevated blood lead concentrations, demonstrating marked biochemical effects of chronic lead intoxication on the erythropoietic system. One week after chelation therapy with EDTA, all subjects had substantially lower blood lead concentrations (Table IV). Urinary ALA decreased toward normal and the in-

hibitory effects on ALAD were greatly reduced. Erythrocyte PROTO concentrations, however, were not significantly affected which is to be expected, since the increased concentration of PROTO is a residual effect of impaired conversion of PROTO to heme in bone marrow erythroblasts, which would not be affected by the chelation with CaEDTA. Activity of another heme pathway enzyme, uroporphyrinogen-I-synthetase, in the erythrocytes from these subjects was within the normal range before chelation therapy and was unaffected by therapy. It was of interest that although the previously mentioned defects of heme biosynthesis were present in all subjects, their hematocrit values were within the normal range (Table IV). Effect of chronic lead exposure on antipyrine half-lives in man. Anti pyri ne , 18 mg/ kg, was administered to each lead-intoxicated subject before and 1 wk after CaEDT A treatment to determine whether there was functional derangement of the hepatic microsomal hemeprotein cytochrome P-450-mediated system. In 7 of 8 subjects (Fig. 2), the antipyrine Ph was shorter after chelation therapy than before. Subject M. D. had a slight increase in antipyrine P/2 after chelation therapy. The mean TVz for all 8 subjects was 10.3 hr before and 8.65 hr after chelation. Except for Subjects H. R. and B. 0., the effect of chronic lead exposure on cytochrome P-450-mediated antipyrine metabolism in the liver was minimal. It should be noted that the mean TI/2 of 10.3 hr and 8.65 hr in these subjects is lower than the previously reported mean TVz (12 to 14 hr) for antipyrine in normal, healthy volunteers. 3 , 10, 20 Discussion

The duration and intensity of action of many drugs and foreign compounds in animals and man depend on the activity of the mixed-function oxidase systems localized in the microsomal fraction of liver homogenates. The hemeprotein, cytochrome P-450, plays a key role, as the terminal oxidase of the hepatic drug-metabolizing enzyme system. Although the effects of lead on the heme biosynthetic pathway in erythropoiesis have been exten-

Volume 19 Number 2

sively studied in a number of laboratories, very few studies have been carried out to determine the effects of lead on heme synthesis in the liver cell. We investigated the effects of acute and chronic lead poisoning on the cytochrome P-450-mediated enzymic activities. Our data show that acute administration of lead to rats caused a marked decrease in the in vitro metabolism of ethylmorphine and aniline and in the in vivo metabolism of hexobarbital. The reduced rates of drug metabolism paralleled the decrease in cytochrome P-450 content of the hepatic microsomes. On the other hand, chronic administration of lead in the diet fed to rats for 12 wk caused no significant changes in the levels of cytochrome P-450 and associated N-demethylase and hydroxylase activities. There was an initial decrease in body weight, but after 3 wk on the diet, body weight gains were similar to those in untreated rats. Phillips, Villeneuve, and Becking 16 observed no changes in pentobarbital-induced sleeping times in rats fed lead acetate for 36 or 85 days. When administered acutely lead may exert a direct action on the hepatic mixedfunction oxidase system since there is a suggestion of involvement of sulfhydryl groups in the integrity and electron-transfer function of cytochrome P_450 19 as well as of NADPHcytochrome c reductase activities. 1s , 21 Lead may also inhibit the synthesis of the hemeprotein, cytochrome P-450; previous studies have shown that lead inhibits ALAD and ferrochelatase activities in erythrocytes,7 both of which are key enzymes in the synthesis of heme, the prosthetic group of cytochrome P-450. These possibilities do not explain the lack of effect of lead administered chronically to rats. The lack of effect may be due to a slow rate of oral absorption or may be due to adaptive responses of the liver to factors causing a decrease in the cytochrome levels. Studies are now in progress to determine whether lead administered acutely and chronically has different effects on the sulfhydryl-containing enzymes involved in heme synthesis in the liver. One way of assessing the functional status of the cytochrome P-450 system in the liver of man is to measure the plasma disappearance

Lead intoxication


rate of antipyrine. Previous studies in this laboratory3 have shown that in children antipyrine half-lives were significantly prolonged during the acute phase of lead poisoning and that therapy of plumbism by chelation led to biochemical remission of the disease and restitution to normal of the metabolic derangement. In our investigation we examined subjects who had had excessive exposure to lead for at least 3 mo with lead levels of 85 to 180 I-tg/ 100 ml blood, demonstrating substantial absorption of lead. They also showed biochemical derangements of lead intoxication. As expected, chelation markedly reduced ALA excretion and reversed ALAD inhibition. On the other hand, PROTO levels were not affected by chelation. Determination of antipyrine half-lives in these 8 workers before and after chelation therapy demonstrated a minimal effect of lead intoxication on this parameter of hepatic P-450 function. The mean TlIz for all 8 subjects was 10.3 hr before and 8.65 hr after chelation. In 2 of the 8 subjects there was a significant decrease in antipyrine TlIz. The mean TV2 values in these subjects were lower than those previously reported for normals. 3, 10, 20 A possible explanation may be the heavy exposure of these subjects to other chemicals contaminating the environment, since most of the demolition work occurs outdoors in urban areas and exposure to such chemicals may have caused elevation of microsomal enzyme activities involved in the detoxification of drugs. These data demonstrate that although the subjects displayed significant hematopoietic manifestations of chronic lead poisoning, the effects of this chronic exposure on the liver microsomal enzymes were minimal. These results are similar to those observed in chronically poisoned rats. The differences in effects of lead exposure on antipyrine half-lives in children, previously reported from this laboratory,3 and in adults may be due to the length of exposure time, but, the possibility cannot be excluded that adults may be more refractory to the hepatic manifestations of lead intoxication than children. It is well known, for example, that children are more susceptible to lead-induced anemia, encephalopathy, and neurologic symp-


Alvares et al.

toms than adults, and this susceptibility, coupled with the observations reported here, and earlier in children,3 support the idea that plumbism may have more direct hepatic consequences in the prepubertal state than previously suspected. We thank Julie Eiseman, Chin Chang, Frances Perez, and Diane Monahan for technical assistance, Dr. Noel H. KlappeI, of BrookIyn Hospital, for referring the lead-poisoned subjects to us, and Dr. Irving J. Selikoff, of the Mt. Sinai School of Medicine, for his support in these studies.

References I. Alvares, A. P., and Mannering, G. J.: Two substrate kinetics of drug metabolizing enzyme systems of hepatic microsomes, Mol. Pharmacol. 6:206-212, 1970. 2. Alvares, A. P., Leigh, S., Cohn, J., and Kappas, A.: Lead and methyl mercury: Effects of acute exposure on cytochrome P-450 and the mixed function oxidase system in the liver, J. Exp. Med. 135:1406-1409, 1972. 3. Alvares, A. P., Kapelner, S., Sassa, S., and Kappas, A.: Drug metabolism in normal children, lead-poisoned children, and normal adults, CUN. PHARMACOL. THER. 17:179-183, 1975. 4. Anders, M. W., and Mannering, G. J.: Inhibition of drug metabolism. I. Kinetics of the inhibition of the N-demethylation of ethylmorphine by 2-diethylaminoethyl 2,2-diphenylvalerate HCL (SKF 525-A) and related compounds, Mol. Pharmacol. 2:319-327, 1966. 5. Brodie, B. B., and Axelrod, J.: The fate of antipyrine in man, J. Pharmacol. Exp. Ther. 98: 97-104, 1950. 6. Brodie, B. B., Axelrod, 1., Soberman, R., and Levy, B. B.: The estimation of antipyrine in biological materials, J. BioI. Chem. 179:25-29, 1949. 7. Chisolm, J. J., Jr.: Disturbances in the biosynthesis of heme in lead intoxication, J. Pediatr. 64: 174- 187, 1964. 8. Granick, J. L., Sassa, S., Granick, S., Levere, R. D., and Kappas, A.: Studies in lead poisoning. n. Correlation between the ratio of activated to inactivated o-aminolevulinic acid dehydratase of whole blood and the blood lead level, Biochem. Med. 8: 149-159, 1973. 9. Imai, Y., Ito, A., and Sato, R.: Evidence for biochemically different types of vesicles in the hepatic microsomal fraction, J. Biochem. (Tokyo) 60:417-428, 1966.

Clinical Pharmacology and Therapeutics

10. Kolmodin, B., Azamoff, D. L., and Sjoqvist, F.: Effect of environmental factors on drug metabolism: Decreased plasma half-life of antipyrine in workers exposed to chlorinated hydrocarbon insecticides, CUN. PHARMACOL. THER. 10:638-642, 1969. I!. Lowry, O. H., Rosebrough, N. J., Farr, A. L., and Randall, R. J.: Protein measurement with the Folin phenol reagent, J. BioI. Chem. 193: 265-275, 1951. 12. Mauzerall, D., and Granick, S.: The occurrence and determination of o-aminolevulinic acid and porphobilinogen in urine, J. BioI. Chem. 219: 435-446, 1956. 13. Nash, T.: The colorimetric estimation of formaldehyde by means of the Hantzch reaction, Biochem. J. 55:417-421, 1953. 14. Omura, T., and Sato, R.: The carbon monoxidebinding pigment of liver microsomes. I. Evidence for its hemoprotein nature, J. BioI. Chem. 239:2370-2378, 1964. 15. PhiIIips, A. H., and Langdon, R. G.: Hepatic triphosphopyridine nucleotide-cytochrome c reductase: Isolation, characterization and kinetic studies, J. BioI. Chem. 237:2652-2660, 1962. 16. Phillips, W. E. J., Villeneuve, D. C., and Becking, G. C.: The effects of lead ingestion on the body burden of DDT, liver vitamin A and microsomal enzyme activity in the rat, Bull. Environ. Contam. Toxicol. 6:570-575, 1971. 17. Remmer, H., Schenkman, J., Estabrook, R. W., Sesame, H., GiIIette, J., Cooper, D. Y., Narasimhulu, S., and Rosenthal, 0.: Drug interaction with hepatic microsomal cytochrome, Mol. Pharmacol. 2:187-190, 1966. 18. Sassa, S., Granick, J. L., Granick, S., Kappas, A., and Levere, R. D.: Studies in lead poisoning. I. Microanalysis of erythrocyte protoporphyrin levels by spectrofturometry in the detection of chronic lead intoxication in the subclinical range, Biochem. Med. 8: 135-148, 1973. 19. Tsai, R., Yu, C. A., Gunsalus, I. C., Peisach, 1., Blumberg, W., Orme-Johnson, W. H., and Beinert, H.: Spin-state changes in cytochrome P-450 CAM on binding of specific substrates, Proc. Natl. Acad. Sci. U.S.A. 66:1157-1163, 1970. 20. Vesell, E. S., and Page, J. G.: Genetic control of the phenobarbital-induced shortening of plasma antipyrine half-lives in man, J. Clin. Invest. 48:2202-2209, 1969. 21. Williams, C. H., Jr., and Kamin, H.: Microsomal triphosphopyridine nucleotide-cytochrome c reductase of liver, J. BioI. Chem. 237:587-595, 1962.

Lead intoxication: effects on cytochrome P-450-mediated hepatic oxidations.

Acute administration of lead to rats caused significant decreases in cytochrome P=450, ethylmorphine N-demethylase, and aniline hydroxylase activities...
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