Liver Enzyme Induction and Cancer

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Liver Enzyme Induction and Cancer

Upcoming Studies (Incomplete Research)

ANDERSON LM. METABOLIC AND PHARMACOLOGICAL DETERMINANTS IN PERINATAL CARCINOGENESIS. Crisp Data Base National Institutes Of Health. Author Address: NCI, NIH

fetuses and newborns may face longterm cancer risks due to early exposure to initiators and promoters (PCBs)
metabolism may be a susceptibility factor in childhood and adult cancers
food mutagens are metabolically activated (to cause cancer) by the enzyme cytochrome P450 1A2 (which is induced by PCBs)
liver and lung tumors in mice started by food contaminants were promoted by a single PCB dose given later (with differences related to time of treatment, type of initiator and sex)

Both exposure to genotoxicants, which initiate tumors, and exposure to bioretained chlorinated hydrocarbon tumor promoters, during the perinatal period may contribute to human cancer risk. A prominent member of the aryl amine food mutagen class, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) is metabolically activated by cytochrome P4501A2. Efforts have begun to assess metabolism as a susceptibility factor in IQ adult and perinatal tumorigenesis. Methods have been developed to permit rapid, simple assay of CYP1A2 from rodent tissues by use of methoxyresorufin as a specific substrate and for consistent Western immunoblot quantification of 1A2 protein. It was found that IQ specifically induced only 1A2 and its activities, by a factor of 2, in a process not controlled by the Ah locus. In an ongoing study of promotion of perinatally-initiated tumors by chlorinated hydrocarbons, liver and lung tumors caused in mice by transplacental or neonatal exposure to the environmental nitrosamines N- nitrosodimethylamine (NDMA) or 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone (NNK) were promoted by a single dose of Aroclor 1254 given later, with differences related to time of treatment, type of initiator, and sex, suggesting possible influences of both quantitative and qualitative factors (cf. project Z01CP05299). A new initiative has involved investigation of effects of preconception exposure of parents on tumors developed in their offspring. In a test of the hypothesis that exposure of fathers to metals may increase risk of cancer in their offspring, male mice were treated with metals typically present in welding fumes, 2 weeks before mating; increased incidence of lung tumors occurred after treatment of fathers with Fe, Ni, Mn, Co, and Cr, with an 8-fold effect (P = 0.02) after Cr (III). Derangement of epigenetic imprinting was proposed as a possible mechanism of this effect. [PCBs were used to induce liver microsomal enzyme production.]

ROBERTSON LW. ACTIVATION OF PCB'S TO GENOTOXINS IN VIVO. Crisp Data Base National Institutes of Health. Author Address: UNIVERSITY OF KENTUCKY MED CTR, 306 HEALTH SCIENCES RES BLDG, LEXINGTON KY 40536-0305

commercial PCB mixtures are complete carcinogens, producing liver cancers in rats and mice, but the mechanisms by which they do so have not been determined
higher chlorinated PCBs promote liver cancer
metabolized lower chlorinated PCBs may be activated by liver enzymes to become cancer initiators
the combination of higher and lower chlorinated PCBs may both cause and promote cancer

Polychlorinated biphenyls (PCBs) are industrial chemicals which persist in our environment. They are found in Superfund sites including the sites in Kentucky and are the direct cause of 5 fish consumption advisories currently in place in Kentucky. The lipophilicy of PCBs and their tendency to bioaccumulate raise concern about the health risks associated with exposure to PCBs and related compounds. Commercial PCB mixtures are complete carcinogens, producing hepatocellular carcinomas in rats and mice, but the mechanisms by which they do so have not been determined. We and others have shown that higher halogenated PCBs (especially, tetra-, penta-, and hexa-chlorinated biphenyls) act as promoters of liver carcinogenesis, but their initiating or DNA damaging activity has not been conclusively demonstrated. Here we present considerable data to support the concept that the lower halogenated biphenyls (especially mono- and di-chlorobiphenyls) may be activated by hepatic enzymes. These PCBs are metabolized to oxygenated species which are electrophilic and which bind to DNA. Of particular interest are quinone metabolites which are oxidation products of dihyroxylated biphenyls. Our preliminary data were generated in in vitro systems. We propose to extend our studies to investigate these activation pathways in the rat. We propose 1) To determine if selected lower halogenated PCBs are metabolized (activated) in vivo to electrophilic species which interact with cellular DNA, forming adducts detectable by sensitive 32P-postlabeling methods, 2) To determine if PCBs activated in vitro and in vivo to electrophiles can act as initiators in an in vivo rat liver initiation model, a modified Solf-Farber protocol, and 3) To determine if those PCBs activated to electrophiles in vitro and in vivo and found positive in the Solt Farber protocol will initiate tow stage hepatocarcinogenesis. Specific lower halogenated PCB initiators and higher halogenated PCB promotors will be used. Jointly these activities may explain why PCB mixtures are complete rodent carcinogens. In these studies rats will be administered highly- purified synthetic PCB congeners. The number and volume of altered hepatic foci, putative preneoplastic lesions, and tumors will be determined. Our project therefore addresses the fundamental question of the mechanisms of toxicity, specifically, genotoxicity of individual PCBs. Clarification of these fundamental questions concerning PCBs as carcinogens, their metabolism in vivo, the nature of their interactions with cellular DNA, their ability to initiate hepatocarcinogenesis and cause liver tumors, will form a basis for the quantitative human health risk assessment for these Superfund Chemicals.

NIMS RW. MECHANISMS AND INTERSPECIES DIFFERENCES IN TUMOR PROMOTION. Crisp Data Base National Institutes Of Health. Author Address: NCI, NIH

induction of the liver enzyme P450 2B (CYP2B) appears to be a reliable predictor of promoting activity for liver cancers in many species
PCBs induce liver enzymes in a direct dose-response relationship, regardless of the type of PCB exposure (continuous or not)
different enzymes are produced by different doses of PCBs

Induction of hepatic cytochrome P450 2B (CYP2B) would appear to be a reliable interspecies predictor of promoting activity for hepatocellular neoplasms. This project is the focus for LCC studies on tumor promotion in non-squamous epithelia. 1,4-Bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) was found to be a profound phenobarbital-type inducer in the rat when administered in the diet for two weeks at 1000 ppm. When extent of induction was related to serum total xenobiotic level, TCPOBOP appeared to be at least as potent, if not more potent, than phenobarbital in the rat. This result, which was confirmed by studies performed with cultured rat hepatocytes, contradicted the commonly held assumption that TCPOBOP is ineffective as a CYP2B inducer in the rat. In other experiments performed with intact F344/NCr rats and primary rat hepatocyte cultures, the potencies for CYP2B induction of the racemate and the individual enantiomers of 5-ethyl-5-phenylhydantoin were found to be essentially equivalent. The induction of CYP2B activity in male B6C3F1 mice by phenobarbital congeners was investigated and compared to the induction in rats by the same compounds. An apparent species difference in relative inducing ability by phenobarbital and 5-ethyl-5- phenylhydantoin was found to reflect differences in pharmacokinetics, not intrinsic inducing ability of these compounds. A direct relationship between level of expression of hepatic drug metabolizing enzymes and polychlorinated biphenyl (PCB) burden in the liver of F344/NCr rats fed Aroclor 1254 was observed, irrespective of the type of exposure (continuous or discontinous). Distinctly different dose-response curves for the induced enzymes were detected, implying different dose thresholds for these effects, many of which are apparently subject to similar transcriptional control. The cotton rat (Sigmodon hispidus) was also found to be exceptionally sensitive to the P450-inducing effects of Aroclor 1254. The ability of phenytoin to promote hepatocellular neoplasia was investigated in D2B6F1 mice. This anticonvulsant elicited profound dose-dependent CYP2B induction and liver tumor promotion.

Studies Without Abstracts

REDDY BS, SHARMA C, MATHEWS L, ENGLE A, LAAKSO K, CHOI K, PUSKA P, KORPELLA R. METABOLIC EPIDEMIOLOGY OF COLON CANCER: FECAL MUTAGENS IN HEALTHY SUBJECTS FROM RURAL KUOPIO AND URBAN HELSINKI, FINLAND. MUTAT RES 152:97-105,1985 [PCBs were used to induce liver microsomal enzyme production.]

GARNER RC, MOULD AJ, LINDSAY-SMITH V, CARTWRIGHT RA, RICHARDS B. MUTAGENIC URINE FROM BLADDER CANCER PATIENTS. LANCET 2:389,1982 [PCBs were used to induce liver microsomal enzyme production.]

YAMAZOE Y, ABU-ZEID M, YAMAUCHI K, KATO R. METABOLIC ACTIVATION OF PYROLYSATE ARYLAMINES BY HUMAN LIVER MICROSOMES. JPN J CANCER RES(GANN) 79:1159-1167,1988 [PCBs were used to induce liver microsomal enzyme production.]

KATO R, YAMAZOE Y, KAMATAKI T. METABOLIC ACTIVATION OF TRYPTOPHAN PYROLYZATES, TRP-P-1 AND TRP-P-2 BY HEPATIC CYTOCHROME P-450, IN: GENETIC AND ENVIRONMENTAL FACTORS IN EXPERIMENTAL AND HUMAN CANCER. PROC INT SYMP PRINCESS TAKAMATSU CANCER RES FUND 10:79-87,1980 [PCBs were used to induce liver microsomal enzyme production.]

HOLLSTEIN M, TALCOTT R, WEI E. QUINOLINE: CONVERSION TO A MUTAGEN BY HUMAN AND RODENT LIVER. J NATL CANCER INST 60:405-410,1978 [PCBs were used to induce liver microsomal enzyme production.]

MONTEITH DK, CONNOR TH, BENVENUTO JA, FAIRCHILD EJ, THEISS JC. STABILITY AND INACTIVATION OF MUTAGENIC DRUGS AND THEIR METABOLITES IN THE URINE OF PATIENTS ADMINISTERED ANTINEOPLASTIC THERAPY. ENVIRON MOL MUTAGEN 10:341-356,1987 [PCBs were used to induce liver microsomal enzyme production.]

YUSPA SH, SHIELDS PG. ETIOLOGY OF CANCER CHEMICAL FACTORS. DE VITA, V. T. JR., S. HELLMAN AND S. A. ROSENBERG (ED.). CANCER: PRINCIPLES AND PRACTICE OF ONCOLOGY, 5TH EDITION, VOLS. 1 AND 2. LXIX+1539P.(VOL. 1); LI+1585P.(VOL. 2) LIPPINCOTT-RAVEN PUBLISHERS: PHILADELPHIA, PENNSYLVANIA, USA. ISBN 0-397-51574-X(SET); ISBN 0-397-51575-8(VOL. 1); ISBN 0-397-51576-6(VOL. 2).; 0 (0). 1997. 185-202. Keywords: BOOK CHAPTER LITERATURE REVIEW HUMAN MOUSE RAT HAMSTER GUINEA-PIG PATIENT ANIMAL MODEL TUMOR BIOLOGY POLYCYCLIC AROMATIC HYDROCARBON CARCINOGEN BUTYLATED HYDROXYTOLUENE POLYCHLORINATED BIPHENYL AFLATOXIN LIVER CANCER LUNG CANCER SKIN CANCER BLADDER CANCER NERVOUS SYSTEM CANCER PROSTATE CANCER DIGESTIVE SYSTEM DISEASE NEOPLASTIC DISEASE RESPIRATORY SYSTEM DISEASE INTEGUMENTARY SYSTEM DISEASE UROLOGIC DISEASE NERVOUS SYSTEM DISEASE REPRODUCTIVE SYSTEM DISEASE-MALE

JONES BK, HATHWAY DE. TISSUE-MEDIATED MUTAGENICITY OF VINYLIDENE CHLORIDE IN SALMONELLA TYPHIMURIUM TA1535. CANCER LETT 5:1-6,1978 [PCBs were used to induce liver microsomal enzyme production.]

KREPINSKY A, BRYANT DW, DAVISON L, YOUNG B, HEDDLE J, MCCALLA DR, DOUGLAS G, MICHALKO K. COMPARISON OF THREE ASSAYS FOR GENETIC EFFECTS OF ANTINEOPLASTIC DRUGS ON CANCER PATIENTS AND THEIR NURSES. ENVIRON MOL MUTAGEN 15:83-92,1990 [PCBs were used to induce liver microsomal enzyme production.]

ELESPURU RK, GONDA SK, MOORE SG. GENETIC AND BIOCHEMICAL FACTORS AFFECTING THE INDUCTION OF BACTERIOPHAGE LAMBDA BY N-NITROSO COMPOUNDS, IN: N-NITROSO COMPOUNDS: OCCURRENCE, BIOLOGICAL EFFECTS AND RELEVANCE TO HUMAN CANCER. IARC(INT AGENCY RES CANCER)SCI PUBL 57:731-739,1984 [PCBs were used to induce liver microsomal enzyme production.]

NEWMAN MA, QUE HEE SS, SCHOENY RS. MUTAGENESIS ASSAYS ON URINES PRODUCED BY PATIENTS ADMINISTERED ADRIAMYCIN AND CYCLOPHOSPHAMIDE. ENVIRON MOL MUTAGEN 16:189-203,1990 [PCBs were used to induce liver microsomal enzyme production.]

CADERNI G, DOLARA P, COSTANTINI A, BARBAGLI G, CALZOLAI A. DETERMINATION OF URINARY MUTAGENS IN PATIENTS WITH URINARY TRACT CANCER. EUR UROL 8:243-246,1982 [PCBs were used to induce liver microsomal enzyme production.]

EVERSON RB, GAD-EL-MAWLA NM, ATTIA MM, CHEVLEN EM, THORGEIRSSON SS, ALEXANDER LA, FLACK PM, STAIANO N, ZIEGLER JL. ANALYSIS OF HUMAN URINE FOR MUTAGENS ASSOCIATED WITH CARCINOMA OF THE BILHARZIAL BLADDER BY THE AMES SALMONELLA PLATE ASSAY: INTERPRETATION EMPLOYING QUANTITATION OF VIABLE LAWN BACTERIA. CANCER (PHILADELPHIA) 51:371-377,1983 [PCBs were used to induce liver microsomal enzyme production.]

SCHIFFMAN MH, ANDREWS AW, VAN TASSELL RL, SMITH L, DANIEL J, ROBINSON A, HOOVER RN, ROSENTHAL J, WEIL R, NAIR PP, SCHWARTZ S, PETTIGREW H, BATIST G, SHAW R, WILKINS TD. CASE-CONTROL STUDY OF COLORECTAL CANCER AND FECAL MUTAGENICITY. CANCER RES 49:3420-3424,1989 [PCBs were used to induce liver microsomal enzyme production.]

Greim H, Deml E, Oesterle D. Drugs and environmental chemicals as promoters. IARC Sci Publ 1984;(56):487-94

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