Immune effects of hexachlorobenzene in the rat: role of metabolism in a 13-week feeding study.
The role of metabolism and porphyria in the immunomodulating effects of hexachlorobenzene (HCB) was investigated. To this end, female Wistar rats received a diet with two different doses of HCB and pentachlorobenzene (PCB), either in combination or not with the cytochrome P450IIIA1 inhibitor, triacetyloleandomycin (TAO). Urinary metabolites and urinary and liver porphyrins were measured at regular intervals and data have been published elsewhere. Skin lesions were scored weekly and after 13 weeks of exposure lymphoid organs were weighed, spleens were examined by morphometry, and serum.(auto)antibody levels were determined by ELISA. The probability of causal relationships between the different parameters was determined by analysis of correlation. HCB caused a dose-dependent increase of the incidence, but not the severity, of skin lesions, and dose-dependently increased weights of popliteal lymph nodes and spleen and serum levels of IgM, IgA, and autoantigen-specific IgM. IgG and IgG autoantibody levels were not changed. The splenomegaly could be attributed to an expansion of all splenic compartments. PCB caused no skin lesions and had only minor, predominantly immunosuppressive effects. TAO virtually lacked immunomodulating activity of its own, hardly affected the induction of skin lesions by HCB, did not change the immune effects of HCB, and suppressed IgG levels when combined with PCB. Comparison of the immunological data with those found in the same rats as to induction of porphyria and biotransformation of HCB and PCB, indicates that the HCB-induced porphyria, being markedly reduced by coadministration of TAO, is not involved in the immunomodulating effects of HCB. The same conclusion could be drawn for the oxidative HCB metabolites, since TAO inhibited their formation, while the same metabolites were formed upon administration of PCB that lacked the immunostimulatory effects of HCB. Therefore, HCB itself, its nonoxidative metabolites, or their precursors are likely candidates for inducing the immune effects. Further, an immune component in the HCB-induced skin lesions, usually associated with dermal porphyrin accumulation, is suggested by the observations that TAO profoundly reduced induction of porphyria, but not of skin lesions and immune effects, by HCB.
Schielen
P
P
Department of Immunotoxicology, Utrecht, University, The Netherlands.
Den Besten
C
C
Vos
J G
JG
Van Bladeren
P J
PJ
Seinen
W
W
Bloksma
N
N
D000276:Adjuvants, Immunologic / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D000918:Antibody Specificity; D001324:Autoantigens / Q000097:blood / Q000276:immunology; D001711:Biotransformation; D001835:Body Weight / Q000187:drug effects; D005260:Female; D006581:Hexachlorobenzene / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity*; D007070:Immunoglobulin A / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D008206:Lymphatic Diseases / Q000139:chemically induced* / Q000276:immunology* / Q000378:metabolism; D008221:Lymphoid Tissue / Q000033:anatomy & histology / Q000187:drug effects / Q000276:immunology; D009929:Organ Size / Q000187:drug effects; D011164:Porphyrias / Q000139:chemically induced* / Q000276:immunology* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012867:Skin / Q000187:drug effects / Q000276:immunology; D012871:Skin Diseases / Q000139:chemically induced* / Q000276:immunology* / Q000378:metabolism; D013163:Splenomegaly / Q000139:chemically induced; D014217:Troleandomycin / Q000494:pharmacology
D000276:Adjuvants, Immunologic; D001324:Autoantigens; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D006581:Hexachlorobenzene; D014217:Troleandomycin