Phototoxicity of protoporphyrin as related to its subcellular localization in mice livers after short-term feeding with griseofulvin

Abstract

In mice, feeding with griseofulvin leads to the rapid accumulation of protoporphyrin in liver mitochondria. When liver mitochondria from mice fed with griseofulvin for 2 days are exposed to irradiation (320-400 nm), uncoupling of oxidative phosphorylation followed by inhibition of respiration occurs at light doses above 3-5 kJ/m2. When combined preparations of mitochondria and lysosomes are irradiated, inactivation of enzymes occurs in the following order: succinate dehydrogenase greater than glutamate dehydrogenase greater than acid phosphatase greater than beta-glucuronidase. Qualitatively, the photodamaging effect of endogenously produced protoporphyrin is indistinguishable from that of externally added protoporphyrin. Quantitatively, however, when protoporphyrin is added externally, more protoporphyrin is taken up by lysosomes, and photoinactivation of the lysosomal enzymes is correspondingly more severe. The results are further evidence that porphyrin-induced photodamage is largely determined by the solubility properties of the porphyrins and the target structures [Sandberg & Romslo (1980) Biochim. Biophys. Acta 593, 187-195], and also that protoporphyrin-induced photodamage is essentially similar whether protoporphyrin is generated endogenously or added exogenously.