Effects of age and obesity on the metabolism of lindane by blacka/a, yellowA^vy/a, and pseudoagoutiA^vy/aphenotypes of (ys × vy) f₁hybrid mice

Abstract

Lindane (gamma-hexachlorocyclohexane) has been shown to produce hepatomas in some strains of mice but not in others. Genetic factors and/or altered metabolism may play a role in the susceptibility to lindane-induced hepatomas. This study reports the effect of age and obesity on the comparative metabolism and disposition of lindane in obese yellow Avy/a and in lean pseudoagouti Avy/a and black a/a phenotypes of (YS x VY) F1 hybrid female mice at 8, 17, 30, 56, and 86 wk of age. At 24 h prior to sacrifice the mice were dosed p.o. with 18 mg lindane (containing 55 microCi [U-14C]lindane/kg). Aging altered the biotransformation of lindane such that while the excretion of lindane and its metabolites declined, the proportion of conjugated and polar metabolites increased. Tissue storage was elevated in older animals. In the yellow Avy/a mice, which are known to have a predisposition to the formation of hepatomas, there was accelerated and prolonged growth, reduced metabolite excretion, a greater proportion of conjugated metabolites, and higher dechlorinase activity compared to that of their pseudoagouti Avy/a and black a/a siblings.

Age‐Related Changes in Carcinogen Metabolism

“…A similar situation appears to hold for lindane, an organochlorine insecticide with carcinogenic potential. Treatment of old mice with lindane results in a decrease in the excretion of chlorophenols and an increase in the major alcohol metabolites 18 . This in vivo result is compatible with studies on enzyme activity in vitro which indicated a decrease in dechlorinase activity and an increase in dehydrogenation in old as compared to young mice.…”

“…The change in glutathione conjugation with age has been examined in vivo for two carcinogens. Production of glutathione conjugates of oxidized metabolites appear to increase in old mice exposed to lindane 18 . In contrast, Borghoff and Birnbaum 85 found that the ability of male rats to conjugate glutathione with allyl isothiocyanate, a bladder carcinogen, 86 did not change with age.…”

“…However, a decrease was not observed in senescent mice, 16 although Hawcroft et al 17 reported a decline in the microsomal phosphatidylcholine content in this species. Recently, Chadwick et al 18 have observed a decrease in phospholipid content in liver microsomes from aging mice. An increase in the relative amount of cholesterol in these membranes has been reported by both Birnbaum 16 and Schmucker et al 19 Whether these compositional changes result in functional differences is unclear since two studies on age‐related changes in hepatic microsomal membrane fluidity came to opposite conclusions 19–20 …”

“…Similar results were observed in rats by Jayaraj et al, 49 in mice by Danis et al, 71 and in miniature swine by Peggins et al 39 This form seems to decline with age in extrahepatic tissue such as the kidney 70 . Although the isozymic form(s) which glucuronidates acetominophen and lindane are not known, Sweeny and Weiner 72 reported a slight increase in the conjugation of acetaminophen with glucuronic acid in hepatocytes isolated from aging rats and mice, and Chadwick et al 18 observed an increase in the glucuronidation of the carcinogen lindane in old mice.…”

“…While glucuronidation is a high capacity, low affinity conjugation pathway, sulfation may be more important at low substrate concentrations 77 . This pathway seems to increase with age in the metabolism of lindane in mice in vivo 18 and in the sulfation of p‐nitrophenol in perfused mouse liver 71 . However, Sweeny and Weiner 72 observed an age‐related decrease in the ability of hepatocytes from both mice and rats to form sulfate conjugates of acetaminophen.…”